BioPAX pathway converted from "SUMOylation of DNA damage response and repair proteins" in the Reactome database.SUMOylation of DNA damage response and repair proteinsSeveral factors that participate in DNA damage response and repair are SUMOylated (reviewed in Dou et al. 2011, Bekker-Jensen and Mailand 2011, Ulrich 2012, Psakhye and Jentsch 2012, Bologna and Ferrari 2013, Flotho and Melchior 2013, Jackson and Durocher 2013). SUMOylation can alter enzymatic activity and protein stability or it can serve to recruit additional factors. For example, SUMOylation of Thymine DNA glycosylase (TDG) causes TDG to lose affinity for its product, an abasic site opposite a G residue, and thus increases turnover of the enzyme. During repair of double-strand breaks SUMO1, SUMO2, SUMO3, and the SUMO E3 ligases PIAS1 and PIAS4 accumulate at double-strand breaks where BRCA1, HERC1, RNF168, MDC1, and TP53BP1 are SUMOylated. SUMOylation of BRCA1 may increase its ubiquitin ligase activity while SUMOylation of MDC1 and HERC2 appears to play a role in recruitment of proteins such as RNF4 and RNF8 to double strand breaks. Similarly SUMOylation of RPA1 (RPA70) recruits RAD51 in the homologous recombination pathway.Authored: May, B, 2013-02-06Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-02-06LEFT-TO-RIGHTSUMOylation of BLM with SUMO2,3BLM is SUMOylated at lysine-317, lysine-331, lysine-344, and lysine-347 with SUMO2,3 (Eladad et al. 2005, Zhu et al. 2008, Ouyang et al. 2009, Ouyang et al. 2013, Hendriks et al. 2014). SUMOylation causes BLM to localize to PML bodies (Eladad et al. 2005). SUMOylated BLM recruits RAD51, which directly binds SUMO, and facilitates the substitution of RAD51 for RPA at stalled replication forks (Ouyang et al. 2009, 2013).Authored: May, B, 2013-09-14Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-14Converted from EntitySet in ReactomeUBE2I:SUMO2,UBE2I:SUMO3Reactome DB_ID: 3899312UBC9_HUMANSUMO2:UBE2ISUMO2 S-glycyl-cys93 UBE2ISUMO-conjugating enzyme UBC9Reactome DB_ID: 2993778nucleoplasmGENE ONTOLOGYGO:0005654SUMO2_HUMANUBE2I-G93-SUMO2Small ubiquitin-related modifier 2Reactome DB_ID: 3730625UniProt:P61956 SUMO2SUMO2SMT3BSMT3H2FUNCTION Ubiquitin-like protein that can be covalently attached to proteins as a monomer or as a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2, CBX4 or ZNF451 (PubMed:26524494). This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Polymeric SUMO2 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins (PubMed:18408734, PubMed:18538659, PubMed:21965678, PubMed:9556629). Plays a role in the regulation of sumoylation status of SETX (PubMed:24105744).SUBUNIT Interacts with SAE2 and UBE2I. Interacts with ZNF451. Identified in a complex with ZNF451 and UBE2I/UBC9, where one ZNF451 interacts with one UBE2I/UBC9 and two SUMO2 chains, one bound to the UBE2I/UBC9 active site and the other to another region of the same UBE2I/UBC9 molecule. Covalently attached to a number of proteins. Interacts with PELP1. Interacts with USP25; the interaction sumoylates USP25. Interacts with SIMC1, CASP8AP2, RNF111 AND SOBP (via SIM domains). Interacts with MTA1. Interacts with Epstein-barr virus BGLF4.TISSUE SPECIFICITY Broadly expressed.PTM Polymeric chains can be formed through Lys-11 cross-linking. Polymeric SUMO2 chains undergo 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination by RNF4.PTM Cleavage of precursor form by SENP1 or SENP2 is necessary for function.PTM Monoubiquitinated N-terminally by UBE2W, which primes it for RNF4-dependent polyubiquitination by the UBE2V1-UBE2N heterodimer.SIMILARITY Belongs to the ubiquitin family. SUMO subfamily.Homo sapiensNCBI Taxonomy9606UniProtP6195693EQUALS-(glycyl)-L-cysteine (Cys-Gly)MODMOD:002111EQUAL93EQUALReactome Database ID Release 753730625Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730625ReactomeR-HSA-37306252Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730625.2Reactomehttp://www.reactome.org1UBC9_HUMANSUMO2-C93-UBE2ISUMO2 S-glycyl-cys93 UBE2ISUMO-conjugating enzyme UBC9Reactome DB_ID: 3730619UniProt:P63279 UBE2IUBE2IUBC9UBCE9FUNCTION Accepts the ubiquitin-like proteins SUMO1, SUMO2, SUMO3, SUMO4 and SUMO1P1/SUMO5 from the UBLE1A-UBLE1B E1 complex and catalyzes their covalent attachment to other proteins with the help of an E3 ligase such as RANBP2, CBX4 and ZNF451. Can catalyze the formation of poly-SUMO chains. Necessary for sumoylation of FOXL2 and KAT5. Essential for nuclear architecture and chromosome segregation. Sumoylates p53/TP53 at 'Lys-386'. Mediates sumoylation of ERCC6 which is essential for its transcription-coupled nucleotide excision repair activity (PubMed:26620705).PATHWAY Protein modification; protein sumoylation.SUBUNIT Forms a complex with SENP6 and UBE2I in response to UV irradiation (PubMed:17704809). Forms a tight complex with RANGAP1 and RANBP2 (PubMed:15378033, PubMed:15608651, PubMed:11853669, PubMed:15931224, PubMed:16732283). Identified in a complex with SUMO2 and UBE2I, where one ZNF451 interacts with one UBE2I and two SUMO2 chains, one bound to the UBE2I active site and the other to another region of the same UBE2I molecule (PubMed:12924945, PubMed:26524494). Interacts with SETX (PubMed:24105744). Interacts with HIPK1 and HIPK2 (By similarity). Interacts with PPM1J (By similarity). Interacts with RASD2 (By similarity). Interacts with TCF3 (By similarity). Interacts with NR2C1; the interaction promotes its sumoylation (By similarity). Interacts with SIAH1 (PubMed:9334332). Interacts with PARP (PubMed:9197546). Interacts with various transcription factors such as TFAP2A, TFAP2B, and TFAP2C (PubMed:12072434). Interacts with AR (PubMed:10383460). Interacts with ETS1 (PubMed:9333025). Interacts with SOX4 (PubMed:16631117). Interacts with RWDD3; the interaction enhances the sumoylation of a number of proteins such as HIF1A and I-kappa-B (PubMed:17956732, PubMed:23469069). Interacts with FOXL2 (PubMed:19744555). Interacts with DNM1l (via its GTPase and B domains); the interaction promotes sumoylation of DNM1L, mainly in its B domain (PubMed:19638400). Interacts with NFATC2IP; this inhibits formation of poly-SUMO chains (PubMed:20077568). Interacts with FHIT (PubMed:11085938). Interacts with PRKRA and p53/TP53 (By similarity). Interacts with UHRF2 (PubMed:23404503). Interacts with NR3C1 and this interaction is enhanced in the presence of RWDD3 (PubMed:23508108, PubMed:25918163). Interacts with MTA1 (PubMed:21965678). Interacts with ZNF451 (PubMed:26524494). Interacts with CPEB3 (By similarity). Interacts with SUMO1, SUMO2 and SUMO3 (PubMed:17466333). Interacts with IPO13 (PubMed:21139563). Interacts with DNMT1 (PubMed:19450230). Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PML-RARA oncoprotein (via the coiled-colied domain); the interaction is required for sumoylation of the PML-RARA oncoprotein (PubMed:15809060). Interacts with ZBED1/hDREF (PubMed:27068747).SUBUNIT (Microbial infection) Interacts with human herpesvirus 6 IE2.SUBUNIT (Microbial infection) Interacts with human adenovirus early E1A protein; this interaction interferes with polysumoylation.SUBUNIT (Microbial infection) Interacts with Epstein-barr virus protein LMP1.TISSUE SPECIFICITY Expressed in heart, skeletal muscle, pancreas, kidney, liver, lung, placenta and brain. Also expressed in testis and thymus.PTM Phosphorylation at Ser-71 significantly enhances SUMOylation activity.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.UniProtP6327993EQUAL1EQUAL158EQUALReactome Database ID Release 753730619Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730619ReactomeR-HSA-37306191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730619.11Reactome Database ID Release 752993778Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993778ReactomeR-HSA-29937781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993778.1ComplexPortalCPX-3049additional informationMIMI:0361UBC9_HUMANSUMO3:UBE2ISUMO3 S-glycyl-cys93 UBE2ISUMO-conjugating enzyme UBC9Reactome DB_ID: 2993782UBC9_HUMANSUMO3-C93-UBE2ISUMO3 S-glycyl-cys93 UBE2ISUMO-conjugating enzyme UBC9Reactome DB_ID: 373062993EQUAL1EQUAL158EQUALReactome Database ID Release 753730629Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730629ReactomeR-HSA-37306291Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730629.11SUMO3_HUMANUBE2I-G92-SUMO3Small ubiquitin-related modifier 3Reactome DB_ID: 3730611UniProt:P55854 SUMO3SUMO3SMT3ASMT3H1FUNCTION Ubiquitin-like protein which can be covalently attached to target lysines either as a monomer or as a lysine-linked polymer. Does not seem to be involved in protein degradation and may function as an antagonist of ubiquitin in the degradation process. Plays a role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Covalent attachment to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by an E3 ligase such as PIAS1-4, RANBP2 or CBX4 (PubMed:11451954, PubMed:18538659, PubMed:21965678). Plays a role in the regulation of sumoylation status of SETX (PubMed:24105744).SUBUNIT Covalently attached to a number of proteins. Interacts with ARNTL/BMAL1 (By similarity). Interacts with USP25 (via ts SIM domain); the interaction sumoylates USP25 and inhibits its ubiquitin hydrolyzing activity. Interacts with SAE2 and UBE2I.TISSUE SPECIFICITY Expressed predominantly in liver.PTM Polymeric chains can be formed through Lys-11 cross-linking.PTM Cleavage of precursor form by SENP1, SENP2 or SENP5 is necessary for function.SIMILARITY Belongs to the ubiquitin family. SUMO subfamily.UniProtP5585492EQUAL1EQUAL92EQUALReactome Database ID Release 753730611Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730611ReactomeR-HSA-37306111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730611.11Reactome Database ID Release 752993782Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993782ReactomeR-HSA-29937821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993782.1ComplexPortalCPX-3050Reactome Database ID Release 753899312Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3899312ReactomeR-HSA-38993121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3899312.14BLMReactome DB_ID: 174881UniProt:P54132 BLMBLMRECQ2RECQL3FUNCTION ATP-dependent DNA helicase that unwinds single- and double-stranded DNA in a 3'-5' direction (PubMed:9388193, PubMed:24816114, PubMed:25901030). Participates in DNA replication and repair (PubMed:12019152, PubMed:21325134, PubMed:23509288). Involved in 5'-end resection of DNA during double-strand break (DSB) repair: unwinds DNA and recruits DNA2 which mediates the cleavage of 5'-ssDNA (PubMed:21325134). Negatively regulates sister chromatid exchange (SCE) (PubMed:25901030). Stimulates DNA 4-way junction branch migration and DNA Holliday junction dissolution (PubMed:25901030). Binds single-stranded DNA (ssDNA), forked duplex DNA and DNA Holliday junction (PubMed:20639533, PubMed:24257077, PubMed:25901030).SUBUNIT Monomer (PubMed:28228481). Homodimer (via N-terminus) (PubMed:28228481). Homotetramer (via N-terminus); dimer of dimers (PubMed:28228481). Homohexamer (via N-terminus) (PubMed:28228481). Self-association negatively regulates DNA unwinding amplitude and rate. Oligomeric complexes dissociate into monomer in presence of ATP (PubMed:28228481). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBS1 protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with ubiquitinated FANCD2. Interacts with RMI complex. Interacts directly with RMI1 (via N-terminal region) component of RMI complex. Interacts with SUPV3L1. Found in a complex, at least composed of BLM, RAD51 and SPIDR; the complex formation is mediated by SPIDR. Interacts with TOP3A (via N-terminal region). Interacts with SPIDR (via C-terminal region); the interaction is direct and required to target BLM to sites of DNA damage.DOMAIN The N-terminal region mediates dimerization and homooligomerization (PubMed:28228481). Both the helicase ATP-binding domain and the helicase C-terminal domain form intramolecular interactions with the HRDC domain in a ATP-dependent manner (PubMed:25901030). The HRDC domain is required for single-stranded DNA (ssDNA) and DNA Holliday junction binding (PubMed:20639533).PTM Phosphorylated in response to DNA damage. Phosphorylation requires the FANCA-FANCC-FANCE-FANCF-FANCG protein complex, as well as the presence of RMI1.SIMILARITY Belongs to the helicase family. RecQ subfamily.UniProtP541321EQUAL1417EQUALReactome Database ID Release 75174881Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174881ReactomeR-HSA-1748811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174881.1BLM_HUMAN4SUMO2,3-BLMBloom syndrome protein ecNumber3.6.4.12/ecNumberReactome DB_ID: 4568883317EQUALsumoylated lysineMODMOD:01149331EQUAL344EQUAL347EQUAL1EQUAL1417EQUALReactome Database ID Release 754568883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568883ReactomeR-HSA-45688832Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568883.2UBE2IUBE2I (UBC9)SUMO-conjugating enzyme UBC9UBC9_HUMANReactome DB_ID: 9124811EQUAL158EQUALReactome Database ID Release 75912481Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=912481ReactomeR-HSA-9124811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-912481.18ACTIVATIONactiveUnit: #Protein7GENE ONTOLOGYGO:0019789gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 753246099Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3246099Reactome Database ID Release 754568914Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568914ReactomeR-HSA-45689141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568914.124027577Pubmed2013BLM SUMOylation regulates ssDNA accumulation at stalled replication forksOuyang, Karen JYagle, Mary KMatunis, Michael JEllis, Nathan AFront Genet 4:16725218447Pubmed2014Uncovering global SUMOylation signaling networks in a site-specific mannerHendriks, Ivo AD'Souza, Rochelle C JYang, BingVerlaan-de Vries, MattyMann, MatthiasVertegaal, Alfred C ONat. Struct. Mol. Biol. 21:927-3618708356Pubmed2008Small ubiquitin-related modifier (SUMO) binding determines substrate recognition and paralog-selective SUMO modificationZhu, JianmeiZhu, ShanshanGuzzo, Catherine MEllis, Nathan ASung, Ki SaChoi, Cheol YongMatunis, Michael JJ. Biol. Chem. 283:29405-1519956565Pubmed2009SUMO modification regulates BLM and RAD51 interaction at damaged replication forksOuyang, Karen JWoo, Leslie LZhu, JianmeiHuo, DezhengMatunis, Michael JEllis, Nathan APLoS Biol. 7:e100025215829507Pubmed2005Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modificationEladad, SoniaYe, Tian-ZhangHu, PengLeversha, MargaretBeresten, SergeyMatunis, Michael JEllis, Nathan AHum. Mol. Genet. 14:1351-65LEFT-TO-RIGHTConjugation of SUMO1 to BRCA1PIAS1,4 SUMOylates BRCA1 with SUMO1PIAS1,4 SUMOylate BRCA1 with SUMO1 at lysine-109 (Morris et al. 2009, Xu et al. 2009). SUMOylation occurs in response to genotoxic stress and double-strand breaks to which PIAS1 and PIAS4 are recruited (Galanty et al. 2009). SUMOylation enhances the ability of BRCA1 to bind and modulate ESR1 (ERalpha) transcriptional activity (Xu et al. 2009). More SUMO2:BRCA1 than SUMO1:BRCA1 is observed in vivo (Morris et al. 2009, Galanty et al. 2009).Authored: May, B, 2013-01-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-19BRCA1Breast cancer type 1 susceptibility proteinReactome DB_ID: 50949UniProt:P38398 BRCA1BRCA1RNF53FUNCTION E3 ubiquitin-protein ligase that specifically mediates the formation of 'Lys-6'-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage. It is unclear whether it also mediates the formation of other types of polyubiquitin chains. The E3 ubiquitin-protein ligase activity is required for its tumor suppressor function. The BRCA1-BARD1 heterodimer coordinates a diverse range of cellular pathways such as DNA damage repair, ubiquitination and transcriptional regulation to maintain genomic stability. Regulates centrosomal microtubule nucleation. Required for normal cell cycle progression from G2 to mitosis. Required for appropriate cell cycle arrests after ionizing irradiation in both the S-phase and the G2 phase of the cell cycle. Involved in transcriptional regulation of P21 in response to DNA damage. Required for FANCD2 targeting to sites of DNA damage. May function as a transcriptional regulator. Inhibits lipid synthesis by binding to inactive phosphorylated ACACA and preventing its dephosphorylation. Contributes to homologous recombination repair (HRR) via its direct interaction with PALB2, fine-tunes recombinational repair partly through its modulatory role in the PALB2-dependent loading of BRCA2-RAD51 repair machinery at DNA breaks. Component of the BRCA1-RBBP8 complex which regulates CHEK1 activation and controls cell cycle G2/M checkpoints on DNA damage via BRCA1-mediated ubiquitination of RBBP8. Acts as a transcriptional activator (PubMed:20160719).ACTIVITY REGULATION The E3 ubiquitin-protein ligase activity is inhibited by phosphorylation by AURKA. Activity is increased by phosphatase treatment.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Heterodimer with BARD1 (PubMed:11573085, PubMed:12890688, PubMed:14976165). Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the MRE11-RAD50-NBN protein (MRN) complex (PubMed:10783165). This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains (PubMed:10783165). Component of the BRCA1-A complex, at least composed of BRCA1, BARD1, UIMC1/RAP80, ABRAXAS1, BRCC3/BRCC36, BABAM2 and BABAM1/NBA1 (PubMed:19261746, PubMed:19261748, PubMed:19261749, PubMed:20351172). Interacts (via the BRCT domains) with ABRAXAS1 (phosphorylated form); this is important for recruitment to sites of DNA damage (PubMed:17525340, PubMed:17643121, PubMed:17643122, PubMed:24316840, PubMed:26778126, PubMed:23269703). Can form a heterotetramer with two molecules of ABRAXAS1 (phosphorylated form) (PubMed:26778126). Component of the BRCA1-RBBP8 complex (PubMed:16101277). Interacts (via the BRCT domains) with RBBP8 ('Ser-327' phosphorylated form); the interaction ubiquitinates RBBP8, regulates CHEK1 activation, and involves RBBP8 in BRCA1-dependent G2/M checkpoint control on DNA damage (PubMed:16818604, PubMed:9811458). Associates with RNA polymerase II holoenzyme (PubMed:9662397). Interacts with SMC1A, NELFB, DCLRE1C, CLSPN (PubMed:11877377, PubMed:15096610, PubMed:15456891, PubMed:11739404). Interacts with CHEK1, CHEK2, BAP1, BRCC3, AURKA, UBXN1 and PCLAF (PubMed:10724175, PubMed:11836499, PubMed:14636569, PubMed:14990569, PubMed:20351172, PubMed:21673012). Interacts (via BRCT domains) with BRIP1 (phosphorylated form) (PubMed:11301010, PubMed:15133502, PubMed:21473589). Interacts with FANCD2 (ubiquitinated form) (PubMed:11239454). Interacts with H2AX (phosphorylated on 'Ser-140') (PubMed:12419185). Interacts (via the BRCT domains) with ACACA (phosphorylated form); the interaction prevents dephosphorylation of ACACA (PubMed:12360400, PubMed:16326698, PubMed:16698035, PubMed:18452305). Part of a BRCA complex containing BRCA1, BRCA2 and PALB2 (PubMed:19369211). Interacts directly with PALB2; the interaction is essential for its function in HRR (PubMed:19369211, PubMed:28319063). Interacts directly with BRCA2; the interaction occurs only in the presence of PALB2 which serves as the bridging protein (PubMed:19369211). Interacts (via the BRCT domains) with LMO4; the interaction represses the transcriptional activity of BRCA1 (PubMed:11751867). Interacts (via the BRCT domains) with CCAR2 (via N-terminus); the interaction represses the transcriptional activator activity of BRCA1 (PubMed:20160719). Interacts with EXD2 (PubMed:26807646). Interacts (via C-terminus) with DHX9; this interaction is direct and links BRCA1 to the RNA polymerase II holoenzyme (PubMed:9662397).TISSUE SPECIFICITY Isoform 1 and isoform 3 are widely expressed. Isoform 3 is reduced or absent in several breast and ovarian cancer cell lines.DOMAIN The BRCT domains recognize and bind phosphorylated pSXXF motif on proteins. The interaction with the phosphorylated pSXXF motif of ABRAXAS1, recruits BRCA1 at DNA damage sites.DOMAIN The RING-type zinc finger domain interacts with BAP1.PTM Phosphorylation at Ser-308 by AURKA is required for normal cell cycle progression from G2 to mitosis. Phosphorylated in response to IR, UV, and various stimuli that cause checkpoint activation, probably by ATM or ATR. Phosphorylation at Ser-988 by CHEK2 regulates mitotic spindle assembly.PTM Autoubiquitinated, undergoes 'Lys-6'-linked polyubiquitination. 'Lys-6'-linked polyubiquitination does not promote degradation.POLYMORPHISM There is evidence that the presence of the rare form of Gln-356-Arg and Leu-871-Pro polymorphisms may be associated with an increased risk for developing ovarian cancer.UniProtP383981EQUAL1863EQUALReactome Database ID Release 7550949Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=50949ReactomeR-HSA-509491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-50949.1SUMO1:C93-UBE2ISUMO1 S-glycyl-cys93 UBE2IReactome DB_ID: 2993783SUMO1_HUMANUBE2I-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 3730622UniProt:P63165 SUMO1SUMO1SMT3CSMT3H3UBL1OK/SW-cl.43FUNCTION Ubiquitin-like protein that can be covalently attached to proteins as a monomer or a lysine-linked polymer. Covalent attachment via an isopeptide bond to its substrates requires prior activation by the E1 complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I, and can be promoted by E3 ligases such as PIAS1-4, RANBP2 or CBX4. This post-translational modification on lysine residues of proteins plays a crucial role in a number of cellular processes such as nuclear transport, DNA replication and repair, mitosis and signal transduction. Involved for instance in targeting RANGAP1 to the nuclear pore complex protein RANBP2. Covalently attached to the voltage-gated potassium channel KCNB1; this modulates the gating characteristics of KCNB1 (PubMed:19223394). Polymeric SUMO1 chains are also susceptible to polyubiquitination which functions as a signal for proteasomal degradation of modified proteins. May also regulate a network of genes involved in palate development. Covalently attached to ZFHX3 (PubMed:24651376).SUBUNIT Covalently attached to KCNB1; UBE2I increases cross-linking with KCNB1 and PIAS1 decreases cross-links with KCNB1 (PubMed:19223394). Interacts with SAE2, RANBP2, PIAS1 and PIAS2. Interacts with PRKN. Covalently attached to a number of proteins such as IKFZ1, PML, RANGAP1, HIPK2, SP100, p53, p73-alpha, MDM2, JUN, DNMT3B and TDG. Also interacts with HIF1A, HIPK2, HIPK3, CHD3, EXOSC9, RAD51 and RAD52. Interacts with USP25 (via ts SIM domain); the interaction weakly sumoylates USP25. Interacts with SIMC1, CASP8AP2, RNF111 AND SOBP (via SIM domains). Interacts with BHLHE40/DEC1. Interacts with RWDD3. Interacts with UBE2I/UBC9 and this interaction is enhanced in the presence of RWDD3. Interacts with MTA1.SUBUNIT (Microbial infection) Interacts with Epstein-barr virus BGLF4.PTM Cleavage of precursor form by SENP1 or SENP2 is necessary for function.PTM Polymeric SUMO1 chains undergo polyubiquitination by RNF4.SIMILARITY Belongs to the ubiquitin family. SUMO subfamily.UniProtP6316597EQUAL2EQUAL97EQUALReactome Database ID Release 753730622Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730622ReactomeR-HSA-37306222Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730622.21UBC9_HUMANSUMO1-C93-UBE2ISUMO1 S-glycyl-cys93 UBE2ISUMO-conjugating enzyme UBC9Reactome DB_ID: 373061793EQUAL1EQUAL158EQUALReactome Database ID Release 753730617Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730617ReactomeR-HSA-37306172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730617.21Reactome Database ID Release 752993783Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993783ReactomeR-HSA-29937832Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993783.2ComplexPortalCPX-3043SUMO1:BRCA1Reactome DB_ID: 3730747SUMO1_HUMANBRCA1-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 373073597EQUAL2EQUAL97EQUALReactome Database ID Release 753730735Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730735ReactomeR-HSA-37307351Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730735.11BRCA1_HUMANSUMO1-K109-BRCA1SUMO1 N-glycyl-lys BRCA1Breast cancer type 1 susceptibility protein ecNumber6.3.2.-/ecNumberReactome DB_ID: 2997644109EQUAL1EQUAL1863EQUALReactome Database ID Release 752997644Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997644ReactomeR-HSA-29976441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997644.11Reactome Database ID Release 753730747Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730747ReactomeR-HSA-37307471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730747.1ACTIVATIONConverted from EntitySet in ReactomePIAS1,4Reactome DB_ID: 2997694PIAS1E3 SUMO-protein ligase PIAS1PIAS1_HUMANReactome DB_ID: 877307UniProt:O75925 PIAS1PIAS1DDXBP1FUNCTION Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. In vitro, binds A/T-rich DNA. The effects of this transcriptional coregulation, transactivation or silencing, may vary depending upon the biological context. Sumoylates PML (at'Lys-65' and 'Lys-160') and PML-RAR and promotes their ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 which in turn promotes PML phosphorylation and degradation (By similarity). Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation. Plays a dynamic role in adipogenesis by promoting the SUMOylation and degradation of CEBPB (By similarity).PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with NCOA2 and AR. Interacts with NR2C1; the interaction promotes its sumoylation (By similarity). Interacts with DDX21, CSRP2, AXIN1, JUN, UBE2I, SUMO1, SATB2, PLAG1, TP53 and STAT1 (dimer), following IFNA1-stimulation. Interacts with SP3 (preferentially when SUMO-modified). Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. Interacts with CHUK/IKKA; this interaction induces PIAS1 phosphorylation. Interacts with PTK2/FAK1; the interaction promotes its sumoylation. Interacts with DDX5. Interacts with PML (By similarity). Interacts with MTA1. Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PRDM1/Blimp-1 (PubMed:28842558).TISSUE SPECIFICITY Expressed in numerous tissues with highest level in testis.DOMAIN The LXXLL motif is a transcriptional coregulator signature.DOMAIN The SP-RING-type domain is required for promoting EKLF sumoylation.PTM Sumoylated.SIMILARITY Belongs to the PIAS family.CAUTION A paper showing that PRMT1-mediated arginine methylation of PIAS1 regulates STAT1 signaling has been retracted, because some of the data was found to be deliberately falsified.UniProtO759251EQUAL651EQUALReactome Database ID Release 75877307Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=877307ReactomeR-HSA-8773071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-877307.1PIAS4E3 SUMO-protein ligase PIAS4 ecNumber6.3.2.-/ecNumberPIAS4_HUMANPIASyPIASgammaReactome DB_ID: 2993789UniProt:Q8N2W9 PIAS4PIAS4PIASGFUNCTION Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulation in various cellular pathways, including the STAT pathway, the p53/TP53 pathway, the Wnt pathway and the steroid hormone signaling pathway. Involved in gene silencing. Mediates sumoylation of CEBPA, PARK7, HERC2, MYB, TCF4 and RNF168. In Wnt signaling, represses LEF1 and enhances TCF4 transcriptional activities through promoting their sumoylations. Enhances the sumoylation of MTA1 and may participate in its paralog-selective sumoylation.PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with AR, AXIN1, GATA2, LEF1, TP53 and STAT1 (IFNG-induced). Binds to AT-rich DNA sequences, known as matrix or scaffold attachment regions (MARs/SARs) (By similarity). Interacts with TICAM1. Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. Interacts with MTA1. Interacts with PRDM1/Blimp-1 (PubMed:28842558).TISSUE SPECIFICITY Highly expressed in testis and, at lower levels, in spleen, prostate, ovary, colon and peripheral blood leukocytes.DOMAIN The LXXLL motif is a coregulator signature that is essential for transcriptional corepression.PTM Sumoylated. Lys-35 is the main site of sumoylation. Sumoylation is required for TCF4 sumoylation and transcriptional activation. Represses LEF1 transcriptional activity. SUMO1 is the preferred conjugate.SIMILARITY Belongs to the PIAS family.UniProtQ8N2W92EQUAL510EQUALReactome Database ID Release 752993789Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993789ReactomeR-HSA-29937891Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993789.1Reactome Database ID Release 752997694Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997694ReactomeR-HSA-29976941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997694.1Reactome Database ID Release 752997675Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997675Reactome Database ID Release 752997709Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997709ReactomeR-HSA-29977091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997709.120016603Pubmed2009Mammalian SUMO E3-ligases PIAS1 and PIAS4 promote responses to DNA double-strand breaksGalanty, YaronBelotserkovskaya, RimmaCoates, JuliaPolo, SophieMiller, Kyle MJackson, Stephen PNature 462:935-919287951Pubmed2009A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cellsXu, JWatkins, TReddy, AReddy, E S PRao, V NInt. J. Oncol. 34:939-4920016594Pubmed2009The SUMO modification pathway is involved in the BRCA1 response to genotoxic stressMorris, Joanna RBoutell, ChrisKeppler, MelanieDensham, RuthWeekes, DanielAlamshah, AminButler, LauraGalanty, YaronPangon, LaurentKiuchi, TaiNg, TonySolomon, EllenNature 462:886-90LEFT-TO-RIGHTConjugation of SUMO2,3 to BRCA1PIAS1,4 SUMOylates BRCA1 with SUMO2,3PIAS1,4 SUMOylate BRCA1 with SUMO2,3 (Galanty et al. 2009, Morris et al. 2009, Vialter et al. 2011, Hendriks et al. 2014). More SUMO2,3-BRCA1 than SUMO1-BRCA1 is observed in vivo (Morris et al. 2009, Galanty et al. 2009). SUMOylation with SUMO2,3 increases in response to oxidative stress (Vialter et al. 2011). SUMOylation of BRCA1 increases its ubiquitin ligase activity (Morris et al. 2009).Authored: May, B, 2013-01-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-19BRCA1_HUMANSUMO2,3-BRCA1SUMO2 N-glycyl-lys BRCA1Breast cancer type 1 susceptibility protein ecNumber6.3.2.-/ecNumberReactome DB_ID: 29976241EQUAL1863EQUALReactome Database ID Release 752997624Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997624ReactomeR-HSA-29976242Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997624.22ACTIVATIONReactome Database ID Release 752997616Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997616ReactomeR-HSA-29976161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2997616.121147198Pubmed2011Cell cycle-dependent conjugation of endogenous BRCA1 protein with SUMO-2/3Vialter, AurélieVincent, AnneDemidem, AïchaMorvan, DanielStepien, GeorgesVenezia, Nicole DallaRio, Pascale GBiochim. Biophys. Acta 1810:432-8LEFT-TO-RIGHTCBX4 (Pc2) SUMOylates CETN2 with SUMO2,3CBX4 (Pc2) in the PRC1 complex SUMOylates CETN2 at an unknown residue with SUMO2,3 (Klein and Nigg 2009). SUMOylation of CETN2 enhances its nuclear localization. Interaction with XPC is also required for nuclear localization of CETN2.Authored: May, B, 2013-09-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-19CETN2Centrin-2CETN2_HUMANReactome DB_ID: 4570490UniProt:P41208 CETN2CETN2CALTCEN2FUNCTION Plays a fundamental role in microtubule organizing center structure and function. Required for centriole duplication and correct spindle formation. Has a role in regulating cytokinesis and genome stability via cooperation with CALM1 and CCP110.FUNCTION Involved in global genome nucleotide excision repair (GG-NER) by acting as component of the XPC complex. Cooperatively with RAD23B appears to stabilize XPC. In vitro, stimulates DNA binding of the XPC:RAD23B dimer.FUNCTION The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex. The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs. The orientation of XPC complex binding appears to be crucial for inducing a productive NER. XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery. Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair.FUNCTION As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores.SUBUNIT Monomer. Homooligomer (PubMed:15356003). Interacts with SFI1 (PubMed:16956364). Interacts with CCP110 (PubMed:16760425). Component of the XPC complex composed of XPC, RAD23B and CETN2 (PubMed:11279143, PubMed:15964821, PubMed:16533048, PubMed:16627479). Component of the nuclear pore complex (NPC)-associated TREX-2 complex (transcription and export complex 2), composed of at least GANP, 2 copies of ENY2, PCID2, SEM1/DSS1, and either centrin CETN2 or centrin CETN3. The TREX-2 complex also associates with ALYREF/ALY and with the nucleoporin NUP153 (PubMed:22307388, PubMed:23591820).MISCELLANEOUS Binds two moles of calcium per mole of protein.SIMILARITY Belongs to the centrin family.UniProtP412081EQUAL172EQUALReactome Database ID Release 754570490Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570490ReactomeR-HSA-45704901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570490.1Centrin-2SUMO2,3-CETN2CETN2_HUMANReactome DB_ID: 45704861EQUAL172EQUALReactome Database ID Release 754570486Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570486ReactomeR-HSA-45704861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570486.12ACTIVATIONactiveUnit: #Protein29PRC1 complexReactome DB_ID: 389114Converted from EntitySet in ReactomeRING1,RNF2RING1A,RING1BReactome DB_ID: 9007201RNF1RING1E3 ubiquitin-protein ligase RING1RING1AReactome DB_ID: 389113UniProt:Q06587 RING1RING1RNF1FUNCTION Constitutes one of the E3 ubiquitin-protein ligases that mediate monoubiquitination of 'Lys-119' of histone H2A, thereby playing a central role in histone code and gene regulation. H2A 'Lys-119' ubiquitination gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility. Compared to RNF2/RING2, it does not have the main E3 ubiquitin ligase activity on histone H2A, and it may rather act as a modulator of RNF2/RING2 activity.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of chromatin-associated Polycomb (PcG) complexes. Interacts with BMI1 (By similarity). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2/RING2 MBLR, L3MBTL2 and YAF2. Interacts with CBX2 and PCGF6. Component of a PRC1-like complex. Component of repressive BCOR complex containing Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RNF2/RING2. Interacts with PCGF2, RNF2; CBX6, CBX7 and CBX8. Interacts with PHC2 (By similarity). Interacts with MN1 (PubMed:31839203).MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtQ065871EQUAL406EQUALReactome Database ID Release 75389113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389113ReactomeR-HSA-3891131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389113.1RNF2RING2E3 ubiquitin-protein ligase RING2RING1BReactome DB_ID: 389119UniProt:Q99496 RNF2RNF2BAP1DINGHIPI3RING1BFUNCTION E3 ubiquitin-protein ligase that mediates monoubiquitination of 'Lys-119' of histone H2A (H2AK119Ub), thereby playing a central role in histone code and gene regulation (PubMed:15386022, PubMed:16359901, PubMed:25519132, PubMed:21772249, PubMed:25355358, PubMed:26151332). H2AK119Ub gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. May be involved in the initiation of both imprinted and random X inactivation (By similarity). Essential component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:16359901, PubMed:26151332). PcG PRC1 complex acts via chromatin remodeling and modification of histones, rendering chromatin heritably changed in its expressibility (PubMed:26151332). E3 ubiquitin-protein ligase activity is enhanced by BMI1/PCGF4 (PubMed:21772249). Acts as the main E3 ubiquitin ligase on histone H2A of the PRC1 complex, while RING1 may rather act as a modulator of RNF2/RING2 activity (Probable). Association with the chromosomal DNA is cell-cycle dependent. In resting B- and T-lymphocytes, interaction with AURKB leads to block its activity, thereby maintaining transcription in resting lymphocytes (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of chromatin-associated Polycomb (PcG) complexes. Component of a number of PRC1-like complexes; these complexes contain either the polycomb group ring finger protein PCGF1, or PCGF2, or PCGF3, or PCGF4, or PCGF5, or PCGF6 (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530, PubMed:26687479, PubMed:26151332). Part of a complex that contains RNF2, UB2D3 and BMI1; within that complex RNF2 and BMI1 form a tight heterodimer, where UB2D3 interacts only with RNF2 (PubMed:21772249, PubMed:25355358). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249). Part of a complex that contains PCGF5, RNF2 and UBE2D3 (PubMed:26151332). Part of a complex that contains AUTS2, PCGF5, RNF2, CSNK2B AND RYBP (PubMed:25519132). Interacts with RYBP, PCGF2, CBX4, CBX6, CBX7 and CBX8 (PubMed:19636380, PubMed:21282530, PubMed:19791798, PubMed:20696397). Interacts with RNF1/RING1, BMI1 and PHC2 (PubMed:15386022, PubMed:16714294). Interaction with RYBP and CBX7 is mutually exclusive; both compete for the same binding site on RNF2 (By similarity). Component of repressive BCOR complex containing a Polycomb group subcomplex at least composed of RYBP, PCGF1, BCOR and RING1 (PubMed:16943429). Interacts with CBX2 and PHC1. Interacts with CHTOP. Interacts with AURKB (By similarity). Part of the E2F6.com-1 complex in G0 phase composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RNF1/RING1, RNF2/RING2, MBLR, L3MBTL2 and YAF2 (PubMed:12004135). Component of some MLL1/MLL complex, at least composed of the core components KMT2A/MLL1, ASH2L, HCFC1/HCF1, WDR5 and RBBP5, as well as the facultative components BAP18, CHD8, E2F6, HSP70, INO80C, KANSL1, LAS1L, MAX, MCRS1, MGA, MYST1/MOF, PELP1, PHF20, PRP31, RING2, RUVB1/TIP49A, RUVB2/TIP49B, SENP3, TAF1, TAF4, TAF6, TAF7, TAF9 and TEX10 (PubMed:15960975). Interacts with RYBP, HIP2 and TFCP2 (PubMed:11513855, PubMed:11865070, PubMed:20696397). Interacts with NUPR1 (PubMed:28720707).PTM Polyubiquitinated in the presence of UBE2D3 (in vitro).PTM Monoubiquitinated, by auto-ubiquitination.MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtQ994961EQUAL336EQUALReactome Database ID Release 75389119Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389119ReactomeR-HSA-3891191Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389119.1Reactome Database ID Release 759007201Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9007201ReactomeR-HSA-90072011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9007201.11Converted from EntitySet in ReactomePHC1,PHC2,PHC3Reactome DB_ID: 9007200PHC1Polyhomeotic-like protein 1HPH1EDR1Early development regulatory protein 1Reactome DB_ID: 389111UniProt:P78364 PHC1PHC1EDR1PH1FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Required for proper control of cellular levels of GMNN expression.SUBUNIT Homodimer. Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). Interacts with RNF2 and CBX7 (By similarity). Interacts with PHC2, PHC2 and BMI1 (By similarity).MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtP783641EQUAL1004EQUALReactome Database ID Release 75389111Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389111ReactomeR-HSA-3891111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389111.1PHC2Polyhomeotic-like protein 2HPH2EDR2Early development regulatory protein 2Reactome DB_ID: 389112UniProt:Q8IXK0 PHC2PHC2EDR2PH2FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.SUBUNIT Component of a PRC1-like complex (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530). Interacts with CBX4 (PubMed:21282530). Interacts with BMI1, PCGF2, PHC1 and RNF2 (PubMed:9121482, PubMed:9199346, PubMed:12167701). Interacts with CHTOP (By similarity). Interacts with the N-terminal region of the SP1 transcription factor and with MAPKAPK2 (PubMed:10976766, PubMed:15094067).DOMAIN HD1 motif interacts with SAM domain of PHC1.MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtQ8IXK01EQUAL858EQUALReactome Database ID Release 75389112Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389112ReactomeR-HSA-3891121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389112.1PHC3Reactome DB_ID: 389116UniProt:Q8NDX5 PHC3PHC3EDR3PH3FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.SUBUNIT Component of a PRC1-like complex.MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtQ8NDX51EQUAL983EQUALReactome Database ID Release 75389116Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389116ReactomeR-HSA-3891161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389116.1Reactome Database ID Release 759007200Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9007200ReactomeR-HSA-90072001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9007200.11SCMH1-2SCMH1 isoform 2Reactome DB_ID: 389122UniProt:Q96GD3-2 SCMH1SCMH1FUNCTION Associates with Polycomb group (PcG) multiprotein complexes; the complex class is required to maintain the transcriptionally repressive state of some genes.SUBUNIT Interacts with the SAM domain of PHC1 via its SAM domain in vitro (By similarity). Associates with a PRC1-like complex.TISSUE SPECIFICITY Strongly expressed in heart, muscle and pancreas. Weakly expressed in brain, placenta, lung, liver and kidney.SIMILARITY Belongs to the SCM family.UniProt IsoformQ96GD3-21EQUAL660EQUALReactome Database ID Release 75389122Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389122ReactomeR-HSA-3891221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389122.11Converted from EntitySet in ReactomeCBX2,CBX4,CBX8Reactome DB_ID: 9007665CBX2Reactome DB_ID: 389110UniProt:Q14781 CBX2CBX2FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) or at 'Lys-27' (H3K27me3) (By similarity). Plays a role in the lineage differentiation of the germ layers in embryonic development (By similarity). Involved in sexual development, acting as activator of NR5A1 expression (PubMed:19361780).SUBUNIT Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). The composition of the PRC1 complex may differ between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1 (By similarity). May interact with H3C15, H3C1 and RNF2 (PubMed:18927235). Interacts (via chromodomain) with histone H3K9Me3 and H3K27me3 (By similarity).DEVELOPMENTAL STAGE Expressed during interphase and metaphase.MISCELLANEOUS The human orthologuous proteins of Drosphila Polycomb group protein Pc, CBX2, CBX4, CBX6, CBX7 and CBX8, show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different complexes.UniProtQ147811EQUAL532EQUALReactome Database ID Release 75389110Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389110ReactomeR-HSA-3891101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389110.1CBX4Reactome DB_ID: 389118UniProt:O00257 CBX4CBX4FUNCTION E3 SUMO-protein ligase which facilitates SUMO1 conjugation by UBE2I (PubMed:12679040). Involved in the sumoylation of HNRNPK, a p53/TP53 transcriptional coactivator, hence indirectly regulates p53/TP53 transcriptional activation resulting in p21/CDKN1A expression. Monosumoylates ZNF131 (PubMed:22825850).FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development (PubMed:12167701, PubMed:19636380, PubMed:21282530). PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:12167701, PubMed:19636380, PubMed:21282530). Binds to histone H3 trimethylated at 'Lys-9' (H3K9me3) (By similarity). Plays a role in the lineage differentiation of the germ layers in embryonic development (By similarity).PATHWAY Protein modification; protein sumoylation.SUBUNIT Interacts with histone H3-K9Me3 (By similarity). Interacts with CHTOP (By similarity). Component of a PRC1-like complex (PubMed:12167701, PubMed:19636380, PubMed:21282530). The composition of the PRC1 complex differs between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1 (By similarity). Self-associates (PubMed:21282530). Interacts with SUV39H1 and HIPK2 (PubMed:12101246, PubMed:17018294). Interacts with CSNK2B (PubMed:21282530). May interact with H3C15, H3C1 and RNF2 (PubMed:18927235). Interacts with SUMO1P1/SUMO5 (PubMed:27211601). Interacts with PRDM1/Blimp-1 (PubMed:28842558).TISSUE SPECIFICITY Ubiquitous.DOMAIN The polyhistidine repeat may act as a targeting signal to nuclear speckles.PTM Phosphorylated on Thr-497 by HIPK2 upon DNA damage. This phosphorylation stimulates E3 SUMO-protein ligase activity and promotes sumoylation on Lys-494, as well as sumoylation of other target proteins, such as HNRNPK.MISCELLANEOUS The human orthologs of the Drosophila Polycomb group protein Pc are CBX2, CBX4, CBX6, CBX7 and CBX8. These show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purified in PubMed:12167701 probably presents a mixture of different complexes containing different Polycomb group proteins.UniProtO002571EQUAL560EQUALReactome Database ID Release 75389118Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389118ReactomeR-HSA-3891181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389118.1CBX8Reactome DB_ID: 389117UniProt:Q9HC52 CBX8CBX8PC3RC1FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility.SUBUNIT Component of a PRC1-like complex. Interacts with RING1 RNF2, PCGF1, PCGF2, PCGF3, BMI1, PCGF5 AND PCGF6. Interacts with MLLT3 and histone H3. Interacts with PHC2 (By similarity).MISCELLANEOUS The human orthologuous proteins of Drosphila Polycomb group protein Pc, CBX2, CBX4, CBX6, CBX7 and CBX8, show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different complexes.UniProtQ9HC521EQUAL389EQUALReactome Database ID Release 75389117Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389117ReactomeR-HSA-3891171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389117.1Reactome Database ID Release 759007665Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9007665ReactomeR-HSA-90076651Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9007665.11Converted from EntitySet in ReactomeBMI1,PCGF2Reactome DB_ID: 9007663BMI1Polycomb complex protein BMI-1PCGF4Polycomb group RING finger protein 4RING finger protein 51RNF51Reactome DB_ID: 389121UniProt:P35226 BMI1BMI1PCGF4RNF51FUNCTION Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:15386022, PubMed:16359901, PubMed:26151332, PubMed:16714294, PubMed:21772249, PubMed:25355358, PubMed:27827373). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249, PubMed:25355358). In the PRC1-like complex, regulates the E3 ubiquitin-protein ligase activity of RNF2/RING2 (PubMed:15386022, PubMed:26151332, PubMed:21772249).SUBUNIT Component of a PRC1-like complex (PubMed:12167701, PubMed:15386022, PubMed:19636380, PubMed:21282530, PubMed:26151332, PubMed:21772249, PubMed:25355358). Identified in a PRC1-like HPRC-H complex with CBX2, CBX4, CBX8, PHC1, PHC2, PHC3 RING1 and RNF2 (PubMed:12167701). Interacts with RNF2/RING2 (PubMed:16714294, PubMed:21772249, PubMed:25355358). Interacts with RING1 (By similarity). Part of a complex that contains RNF2, UB2D3 and BMI1, where RNF2 and BMI1 form a tight heterodimer, and UB2D3 interacts only with RNF2 (PubMed:21772249, PubMed:25355358). The complex composed of RNF2, UB2D3 and BMI1 binds nucleosomes, and has activity only with nucleosomal histone H2A (PubMed:21772249, PubMed:25355358). Interacts with CBX7 and CBX8 (PubMed:19636380). Interacts with SPOP (PubMed:15897469). Part of a complex consisting of BMI1, CUL3 and SPOP (PubMed:15897469). Interacts with E4F1 (PubMed:16882984). Interacts with PHC2 (PubMed:9121482, PubMed:9199346, PubMed:27827373).PTM Monoubiquitinated (By similarity). May be polyubiquitinated; which does not lead to proteasomal degradation.MISCELLANEOUS The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different PRC1-like complexes.UniProtP352261EQUAL326EQUALReactome Database ID Release 75389121Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389121ReactomeR-HSA-3891211Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389121.1PCGF2Reactome DB_ID: 389115UniProt:P35227 PCGF2PCGF2MEL18RNF110ZNF144FUNCTION Transcriptional repressor. Binds specifically to the DNA sequence 5'-GACTNGACT-3'. Has tumor suppressor activity. May play a role in control of cell proliferation and/or neural cell development. Regulates proliferation of early T progenitor cells by maintaining expression of HES1. Also plays a role in antero-posterior specification of the axial skeleton and negative regulation of the self-renewal activity of hematopoietic stem cells (By similarity). Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:26151332). Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity (PubMed:26151332).SUBUNIT Exists as both a monomer and homodimer (By similarity). Component of a PRC1-like complex (PubMed:19636380, PubMed:21282530, PubMed:26151332). Interacts with CBX8, RING1 AND RNF2 (PubMed:19636380). Interacts with CBX7 (By similarity). Interacts with PHC2 (By similarity).TISSUE SPECIFICITY Detected in all tissues examined with high expression found in placenta lung and kidney and low expression, in liver, pancreas and skeletal muscle.PTM Phosphorylated. Homodimer formation is regulated by phosphorylation with only unphosphorylated proteins forming homodimers.UniProtP352271EQUAL344EQUALReactome Database ID Release 75389115Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389115ReactomeR-HSA-3891151Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389115.1Reactome Database ID Release 759007663Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9007663ReactomeR-HSA-90076631Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9007663.11Reactome Database ID Release 75389114Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=389114ReactomeR-HSA-3891142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-389114.2Reactome Database ID Release 753108185Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108185Reactome Database ID Release 754570463Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570463ReactomeR-HSA-45704632Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570463.219706679Pubmed2009SUMO-dependent regulation of centrin-2Klein, Ulf RNigg, EAJ. Cell. Sci. 122:3312-21LEFT-TO-RIGHTSMC5-SMC6 Complex SUMOylates Cohesin with SUMO1The NSMCE2 (NSE2, MMS21) subunit of the SMC5/6 complex SUMOylates the RAD21 and STAG2 subunits of cohesin with SUMO1 (Potts et al. 2006 supplementary data, reviewed in Stephan et al 2011). RAD21 (SCC1) is SUMOylated at several lysines (Wu et al. 2012). SUMOylation of RAD21 occurs during DNA damage repair and is necessary for sister chromatid recombination (Wu et al. 2012).Authored: May, B, 2013-02-06Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-02-06Cohesin ComplexReactome DB_ID: 1641505SMC3Structural maintenance of chromosomes protein 3Reactome DB_ID: 163009UniProt:Q9UQE7 SMC3SMC3BAMBMHCSPG6SMC3L1FUNCTION Central component of cohesin, a complex required for chromosome cohesion during the cell cycle. The cohesin complex may form a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. Cohesion is coupled to DNA replication and is involved in DNA repair. The cohesin complex plays also an important role in spindle pole assembly during mitosis and in chromosomes movement.SUBUNIT Forms a heterodimer with SMC1A or SMC1B in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21. Also found in meiosis-specific cohesin complexes (PubMed:11076961). Found in a complex with SMC1A, CDCA5 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NUMA1, and forms a ternary complex with KIF3B and KIFAP3, suggesting a function in tethering the chromosomes to the spindle pole and in chromosome movement (PubMed:9506951, PubMed:11590136). Interacts with PDS5A and WAPL; regulated by SMC3 acetylation (PubMed:19907496). Interacts (via SMC hinge domain) with KIAA1328 (via N- and C-terminal domains) (PubMed:15656913). Interacts with DDX11 (PubMed:17105772). Found in a cohesin complex with SMC1A, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566). Interacts with MXI1, MXD3, MXD4, SYCP2, RPGR and STAG3 (By similarity).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC1A or SMC1B, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated at Ser-1083 in a SPO11-dependent manner.PTM Acetylation at Lys-105 and Lys-106 by ESCO1 is important for genome stability and S phase sister chromatid cohesion. Regulated by DSCC1, it is required for processive DNA synthesis, coupling sister chromatid cohesion establishment during S phase to DNA replication. Deacetylation by HDAC8, regulates release of the cohesin complex from chromatin.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC3 subfamily.CAUTION Was originally isolated as a proteoglycan protein (explaining its name). Although not excluded, such secreted function is not clear.UniProtQ9UQE71EQUAL1217EQUALReactome Database ID Release 75163009Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163009ReactomeR-HSA-1630091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163009.11SA2STAG2Cohesin subunit SA-2SCC3 homolog 2Reactome DB_ID: 163046UniProt:Q8N3U4 STAG2STAG2SA2FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Interacts directly with RAD21 in cohesin complex. Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG2 is mutually exclusive with STAG1 and STAG3.PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family.UniProtQ8N3U41EQUAL1231EQUALReactome Database ID Release 75163046Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163046ReactomeR-HSA-1630461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163046.11SA1STAG1Cohesin subunit SA-1SCC3 homolog 1Reactome DB_ID: 163016UniProt:Q8WVM7 STAG1STAG1SA1SCC3FUNCTION Component of cohesin complex, a complex required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis.SUBUNIT Cohesin complexes are composed of a heterodimer between a SMC1 protein (SMC1A or SMC1B) and SMC3, which are attached via their hinge domain, and RAD21 which link them at their heads, and one STAG protein (STAG1, STAG2 or STAG3). In cohesin complexes, STAG1 is mutually exclusive with STAG2 and STAG3 (PubMed:11076961). Interacts directly with RAD21 in cohesin complex (By similarity). Found in a cohesin complex with SMC1A, SMC3 and RAD21 (PubMed:22628566).PTM Phosphorylated by PLK1. The large dissociation of cohesin from chromosome arms during prophase is partly due to its phosphorylation (By similarity).SIMILARITY Belongs to the SCC3 family.UniProtQ8WVM71EQUAL1258EQUALReactome Database ID Release 75163016Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163016ReactomeR-HSA-1630161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163016.11SMC1ASMC1 (BAA11495)Structural maintenance of chromosome 1-like 1 protein (SMC1alpha protein) (SB1.8/DXS423E protein) (Sb1.8)Structural maintenance of chromosome 1-like 1 proteinSMC1alpha proteinSB1.8/DXS423E proteinSb1.8Reactome DB_ID: 64561UniProt:Q14683 SMC1ASMC1ADXS423EKIAA0178SB1.8SMC1SMC1L1FUNCTION Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint.SUBUNIT Forms a heterodimer with SMC3 in cohesin complexes (PubMed:22628566). Cohesin complexes are composed of the SMC1 (SMC1A or SMC1B) and SMC3 heterodimer attached via their SMC hinge domain, RAD21 which link them, and one STAG protein (STAG1, STAG2 or STAG3), which interacts with RAD21 (PubMed:11076961). In germ cell cohesin complexes, SMC1A is mutually exclusive with SMC1B (By similarity). Interacts with BRCA1 (PubMed:11877377). Found in a complex with CDCA5, SMC3 and RAD21, PDS5A/SCC-112 and PDS5B/APRIN (PubMed:15837422). Interacts with NDC80 (PubMed:9295362, PubMed:10409732,). Interacts with BRAT1 (PubMed:22977523). Found in a complex containing POLE and SMC3. Interacts with RPGR, STAG3 and SYCP2 (By similarity). Found in a cohesin complex with SMC3, STAG1 and RAD21 (PubMed:22628566). The SMC1A-SMC3 heterodimer interacts with the NIPBL-MAU2 heterodimer (PubMed:22628566).DOMAIN The flexible SMC hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC3, forming a V-shaped heterodimer. The two heads of the heterodimer are then connected by different ends of the cleavable RAD21 protein, forming a ring structure (By similarity).PTM Ubiquitinated by the DCX(DCAF15) complex, leading to its degradation.PTM Phosphorylated by ATM upon ionizing radiation in a NBS1-dependent manner. Phosphorylated by ATR upon DNA methylation in a MSH2/MSH6-dependent manner. Phosphorylation of Ser-957 and Ser-966 activates it and is required for S-phase checkpoint activation.MISCELLANEOUS Mutated Cornelia de Lange cell lines display genomic instability and sensitivity to ionizing radiation and interstrand cross-linking agents.SIMILARITY Belongs to the SMC family. SMC1 subfamily.UniProtQ146831EQUAL1233EQUALReactome Database ID Release 7564561Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=64561ReactomeR-HSA-645611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-64561.11RAD21Reactome DB_ID: 163042UniProt:O60216 RAD21RAD21HR21KIAA0078NXP1SCC1SUBUNIT Component of the cohesin complex, which consists of an SMC1A/B and SMC3 heterodimer core and 2 non-Smc subunits RAD21 and STAG1/SA1, STAG2/SA2 or STAG3/SA3 (PubMed:10931856, PubMed:11590136, PubMed:22628566, PubMed:25575569). The cohesin complex interacts with NUMA1 (PubMed:11590136). The cohesin complex also interacts with CDCA5, PDS5A and PDS5B; this interaction might regulate the ability of the cohesin complex to mediate sister chromatid cohesion (PubMed:15837422). The interaction with PDS5B is direct and is stimulated by STAG1/SA1 (PubMed:19696148). The cohesin complex interacts with the cohesin loading complex subunits NIPBL/Scc2 (via HEAT repeats) and MAU2/Scc4 (PubMed:22628566). The cohesin complex interacts with DDX11/ChIR1 (PubMed:17105772). Directly interacts with WAPL; this interaction is stimulated by STAG1/SA1 (PubMed:19696148).TISSUE SPECIFICITY Expressed in the gut (at protein level).DEVELOPMENTAL STAGE Regulated in a cell cycle-dependent manner: expression increases in late S phase and reaches maximum in G2 at the nucleotide level (PubMed:8812457). Not regulated during the cell cycle (at protein level) (PubMed:11073952).DOMAIN The C-terminal part associates with the head of SMC1A, while the N-terminal part binds to the head of SMC3.PTM Cleaved by separase/ESPL1 at the onset of anaphase; this cleavage is required for sister chromatid separation and cytokinesis (PubMed:11509732). Cleaved by caspase-3/CASP3 or caspase-7/CASP7 at the beginning of apoptosis (PubMed:12417729, PubMed:11875078).PTM Phosphorylated; becomes hyperphosphorylated in M phase of cell cycle. The large dissociation of cohesin from chromosome arms during prophase may be partly due to its phosphorylation by PLK1.SIMILARITY Belongs to the rad21 family.UniProtO602161EQUAL631EQUALReactome Database ID Release 75163042Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=163042ReactomeR-HSA-1630421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-163042.11Reactome Database ID Release 751641505Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1641505ReactomeR-HSA-16415051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1641505.1ComplexPortalCPX-5991ComplexPortalCPX-59892SUMOylated CohesinReactome DB_ID: 3108231SUMO1:RAD21Reactome DB_ID: 3826600SUMO1-K-RAD21SUMO1 N-glycyl-lys RAD21Reactome DB_ID: 31081831EQUAL631EQUALReactome Database ID Release 753108183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108183ReactomeR-HSA-31081831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3108183.11SUMO1_HUMANRAD21-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 382657497EQUAL2EQUAL97EQUALReactome Database ID Release 753826574Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3826574ReactomeR-HSA-38265741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3826574.11Reactome Database ID Release 753826600Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3826600ReactomeR-HSA-38266001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3826600.111SUMO1:STAG2Reactome DB_ID: 3826642SUMO1_HUMANSTAG2-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 382664597EQUAL2EQUAL97EQUALReactome Database ID Release 753826645Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3826645ReactomeR-HSA-38266451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3826645.11SA2SUMO1-K-STAG2SUMO1 N-glycyl-lys STAG2Cohesin subunit SA-2SCC3 homolog 2Reactome DB_ID: 31081871EQUAL1231EQUALReactome Database ID Release 753108187Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108187ReactomeR-HSA-31081871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3108187.11Reactome Database ID Release 753826642Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3826642ReactomeR-HSA-38266421Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3826642.1111Reactome Database ID Release 753108231Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108231ReactomeR-HSA-31082311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3108231.12ACTIVATIONactiveUnit: #Protein44SMC5-SMC6 ComplexReactome DB_ID: 2993768NDNL2NSMCE3Melanoma-associated antigen G1MAGG1_HUMANReactome DB_ID: 2993761UniProt:Q96MG7 NSMCE3NSMCE3HCA4MAGEG1NDNL2FUNCTION Component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination (PubMed:20864041, PubMed:27427983). The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). In vitro enhances ubiquitin ligase activity of NSMCE1. Proposed to act through recruitment and/or stabilization of the Ubl-conjugating enzyme (E2) at the E3:substrate complex (PubMed:20864041). May be a growth suppressor that facilitates the entry of the cell into cell cycle arrest (By similarity).SUBUNIT Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer (PubMed:18086888). Interacts with PJA1 (PubMed:20864041). Interacts with E2F1 (via C-terminus) (By similarity). Interacts with NGFR (via C-terminus) (By similarity). Interacts with NSMCE1 (PubMed:18086888, PubMed:21364888, PubMed:20864041, PubMed:27427983). Interacts with NSMCE4 (PubMed:20864041, PubMed:27427983). Interacts with SMC6 (PubMed:18086888). Interacts with EID3 (PubMed:21364888).TISSUE SPECIFICITY Ubiquitous.UniProtQ96MG71EQUAL304EQUALReactome Database ID Release 752993761Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993761ReactomeR-HSA-29937612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993761.21NSMCE2E3 SUMO-protein ligase NSE2 ecNumber6.3.2.-/ecNumberNSE2_HUMANReactome DB_ID: 2993759UniProt:Q96MF7 NSMCE2NSMCE2C8orf36MMS21FUNCTION E3 SUMO-protein ligase component of the SMC5-SMC6 complex, a complex involved in DNA double-strand break repair by homologous recombination. Is not be required for the stability of the complex. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Acts as an E3 ligase mediating SUMO attachment to various proteins such as SMC6L1 and TRAX, the shelterin complex subunits TERF1, TERF2, TINF2 and TERF2IP, and maybe the cohesin components RAD21 and STAG2. Required for recruitment of telomeres to PML nuclear bodies. SUMO protein-ligase activity is required for the prevention of DNA damage-induced apoptosis by facilitating DNA repair, and for formation of APBs in ALT cell lines. Required for sister chromatid cohesion during prometaphase and mitotic progression.PATHWAY Protein modification; protein sumoylation.SUBUNIT Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3.PTM Sumoylated, possibly via autosumoylation.SIMILARITY Belongs to the NSE2 family.UniProtQ96MF71EQUAL247EQUALReactome Database ID Release 752993759Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993759ReactomeR-HSA-29937591Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993759.11SMC5Structural maintenance of chromosomes protein 5SMC5_HUMANReactome DB_ID: 2993751UniProt:Q8IY18 SMC5SMC5KIAA0594SMC5L1FUNCTION Core component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. Required for sister chromatid cohesion during prometaphase and mitotic progression; the function seems to be independent of SMC6. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome (PubMed:26983541).SUBUNIT Forms a heterodimer with SMC6 (PubMed:11408570). Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3 (PubMed:18086888). Interacts with NSMCE2 (PubMed:16055714). Interacts with SLF2; this interaction induces an association of the SLF1-SLF2 complex with the SMC5-SMC6 complex (PubMed:25931565). Interacts with RAD18; this interaction is increased in a SLF1 or SLF2-dependent manner (PubMed:25931565).SUBUNIT (Microbial infection) SMC5-SMC6 complex interacts with Hepatitis B X protein.TISSUE SPECIFICITY Widely expressed (PubMed:11408570). Strongly expressed in testis (PubMed:11408570).DOMAIN The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC6, forming a V-shaped heterodimer.PTM Sumoylated.PTM Ubiquitinated.PTM (Microbial infection) SMC5-SMC6 complex is degraded by the activity of Hepatitis B X protein.SIMILARITY Belongs to the SMC family. SMC5 subfamily.UniProtQ8IY181EQUAL1101EQUALReactome Database ID Release 752993751Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993751ReactomeR-HSA-29937511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993751.11Converted from EntitySet in ReactomeEID3,NSMCE4AReactome DB_ID: 2993753EID3EP300-interacting inhibitor of differentiation 3EID3_HUMANReactome DB_ID: 2993760UniProt:Q8N140 EID3EID3FUNCTION Tissue-specific component of the SMC5-SMC6 complex, a complex involved in repair of DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination and mediates sumoylation of shelterin complex (telosome) components.FUNCTION Acts as a repressor of nuclear receptor-dependent transcription possibly by interfering with CREBBP-dependent coactivation. May function as a coinhibitor of other CREBBP/EP300-dependent transcription factors.SUBUNIT Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3; EID3 seems to be a testis-specific subunit. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer. Homodimer, and heterodimer with EID2 (By similarity). Interacts with the C-terminal region of CREBBP.TISSUE SPECIFICITY Highly expressed in testis.SIMILARITY Belongs to the NSE4 family.UniProtQ8N1401EQUAL333EQUALReactome Database ID Release 752993760Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993760ReactomeR-HSA-29937601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993760.1NSMCE4ANon-structural maintenance of chromosomes element 4 homolog ANSE4A_HUMANReactome DB_ID: 2993757UniProt:Q9NXX6 NSMCE4ANSMCE4AC10orf86PP4762FUNCTION Component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Is involved in positive regulation of response to DNA damage stimulus.SUBUNIT Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5:SMC6 heterodimer (PubMed:18086888). Interacts with NSMCE3 (PubMed:27427983).SIMILARITY Belongs to the NSE4 family.UniProtQ9NXX61EQUAL385EQUALReactome Database ID Release 752993757Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993757ReactomeR-HSA-29937571Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993757.1Reactome Database ID Release 752993753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993753ReactomeR-HSA-29937531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993753.11SMC6Structural maintenance of chromosomes protein 6SMC6_HUMANReactome DB_ID: 2993777UniProt:Q96SB8 SMC6SMC6SMC6L1FUNCTION Core component of the SMC5-SMC6 complex, a complex involved in DNA double-strand breaks by homologous recombination. The complex may promote sister chromatid homologous recombination by recruiting the SMC1-SMC3 cohesin complex to double-strand breaks. The complex is required for telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines and mediates sumoylation of shelterin complex (telosome) components which is proposed to lead to shelterin complex disassembly in ALT-associated PML bodies (APBs). Required for recruitment of telomeres to PML nuclear bodies. SMC5-SMC6 complex may prevent transcription of episomal DNA, such as circular viral DNA genome (PubMed:26983541).SUBUNIT Forms a heterodimer with SMC5 (PubMed:11408570). Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3 (PubMed:18086888). Interacts with NSMCE1 (PubMed:14701739). Interacts with NSMCE2 (PubMed:16055714). Interacts with SLF1 (PubMed:25931565). Interacts with SLF2 (PubMed:25931565). Interacts with RAD18 (PubMed:25931565).SUBUNIT (Microbial infection) SMC5-SMC6 complex interacts with Hepatitis B X protein.TISSUE SPECIFICITY Widely expressed (PubMed:11408570). Strongly expressed in testis (PubMed:11408570).DOMAIN The flexible hinge domain, which separates the large intramolecular coiled coil regions, allows the heterotypic interaction with the corresponding domain of SMC5, forming a V-shaped heterodimer.PTM Phosphorylated.PTM Sumoylated by NSMCE2/MMS21.PTM Ubiquitinated.PTM (Microbial infection) SMC5-SMC6 complex is degraded by the activity of Hepatitis B X protein.SIMILARITY Belongs to the SMC family. SMC6 subfamily.UniProtQ96SB81EQUAL1091EQUALReactome Database ID Release 752993777Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993777ReactomeR-HSA-29937771Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993777.11NSMCE1Non-structural maintenance of chromosomes element 1 homologNSE1_HUMANReactome DB_ID: 2993767UniProt:Q8WV22 NSMCE1NSMCE1HSPC333HSPC337FUNCTION RING-type zinc finger-containing E3 ubiquitin ligase that assembles with melanoma antigen protein (MAGE) to catalyze the direct transfer of ubiquitin from E2 ubiquitin-conjugating enzyme to a specific substrate. Within MAGE-RING ubiquitin ligase complex, MAGE stimulates and specifies ubiquitin ligase activity likely through recruitment and/or stabilization of the E2 ubiquitin-conjugating enzyme at the E3:substrate complex. Involved in maintenance of genome integrity, DNA damage response and DNA repair (PubMed:29225034, PubMed:20864041). NSMCE3/MAGEG1 and NSMCE1 ubiquitin ligase are components of SMC5-SMC6 complex and may positively regulate homologous recombination-mediated DNA repair (PubMed:18086888). MAGEF1-NSMCE1 ubiquitin ligase promotes proteasomal degradation of MMS19, a key component of the cytosolic iron-sulfur protein assembly (CIA) machinery. Down-regulation of MMS19 impairs the activity of several DNA repair and metabolism enzymes such as ERCC2/XPD, FANCJ, RTEL1 and POLD1 that require iron-sulfur clusters as cofactors (PubMed:29225034).SUBUNIT Component of the SMC5-SMC6 complex which consists at least of SMC5, SMC6, NSMCE2, NSMCE1, NSMCE4A or EID3 and NSMCE3. NSMCE1, NSMCE4A or EID3 and NSMCE3 probably form a subcomplex that bridges the head domains of the SMC5-SMC6 heterodimer (PubMed:18086888, PubMed:20864041). Interacts with NSMCE3 (PubMed:27427983). Interacts with MAGEF1 (PubMed:29225034).PTM Ubiquitinated.SIMILARITY Belongs to the NSE1 family.UniProtQ8WV221EQUAL266EQUALReactome Database ID Release 752993767Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993767ReactomeR-HSA-29937671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993767.11Reactome Database ID Release 752993768Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993768ReactomeR-HSA-29937681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993768.1Reactome Database ID Release 753108233Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108233Reactome Database ID Release 753108212Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108212ReactomeR-HSA-31082122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3108212.222751501Pubmed2012Scc1 sumoylation by Mms21 promotes sister chromatid recombination through counteracting WaplWu, NanKong, XiangduoJi, ZhejianZeng, WeihuaPotts, Patrick RyanYokomori, KyokoYu, HongtaoGenes Dev. 26:1473-8516810316Pubmed2006Human SMC5/6 complex promotes sister chromatid homologous recombination by recruiting the SMC1/3 cohesin complex to double-strand breaksPotts, Patrick RyanPorteus, Matthew HYu, HongtaoEMBO J. 25:3377-8821550342Pubmed2011The Nse2/Mms21 SUMO ligase of the Smc5/6 complex in the maintenance of genome stabilityStephan, Anna KKliszczak, MaciejMorrison, CGFEBS Lett. 585:2907-13LEFT-TO-RIGHTPIAS4 SUMOylates HERC2 with SUMO1PIAS4 SUMOylates HERC2 at an unknown lysine residue with SUMO1 (Danielsen et al. 2012). HERC2 binds SUMO1 and is then SUMOylated. SUMOylation of HERC2 promotes binding to RNF8 at double-strand breaks in DNA.Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-13HERC2E3 ubiquitin-protein ligase HERC2 ecNumber6.3.2.-/ecNumberHERC2_HUMANReactome DB_ID: 4551680UniProt:O95714 HERC2HERC2FUNCTION E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes. Recruited to sites of DNA damage in response to ionizing radiation (IR) and facilitates the assembly of UBE2N and RNF8 promoting DNA damage-induced formation of 'Lys-63'-linked ubiquitin chains. Acts as a mediator of binding specificity between UBE2N and RNF8. Involved in the maintenance of RNF168 levels. E3 ubiquitin-protein ligase that promotes the ubiquitination and proteasomal degradation of XPA which influences the circadian oscillation of DNA excision repair activity. By controlling the steady-state expression of the IGF1R receptor, indirectly regulates the insulin-like growth factor receptor signaling pathway (PubMed:26692333).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts (when phosphorylated at Thr-4827 and sumoylated) with RNF8 (via FHA domain); this interaction increases after ionizing radiation (IR) treatment. Interacts with XPA. Interacts with NEURL4. Via its interaction with NEURL4, may indirectly interact with CCP110 and CEP97.DOMAIN The ZZ-type zinc finger mediates binding to SUMO1, and at low level SUMO2.DOMAIN The RCC1 repeats are grouped into three seven-bladed beta-propeller regions.PTM Phosphorylation at Thr-4827 is required for interaction with RNF8.PTM Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs), promoting the interaction with RNF8.POLYMORPHISM Genetic variants in HERC2 define the skin/hair/eye pigmentation variation locus 1 (SHEP1) [MIM:227220]; also known as skin/hair/eye pigmentation type 1, blue/nonblue eyes or skin/hair/eye pigmentation type 1, blue/brown eyes or skin/hair/eye pigmentation type 1, blond/brown hair or eye color, brown/blue or eye color, blue/nonblue or eye color type 3 (EYCL3) or brown eye color type 2 (BEY2) or hair color type 3 (HCL3). Hair, eye and skin pigmentation are among the most visible examples of human phenotypic variation, with a broad normal range that is subject to substantial geographic stratification. In the case of skin, individuals tend to have lighter pigmentation with increasing distance from the equator. By contrast, the majority of variation in human eye and hair color is found among individuals of European ancestry, with most other human populations fixed for brown eyes and black hair.MISCELLANEOUS A regulatory element withinin an intron of the HERC2 gene inhibits OCA2 promoter. There are several single nucleotide polymorphisms within the OCA2 gene and within the HERC2 gene that have a statistical association with human eye color.UniProtO957141EQUAL4834EQUALReactome Database ID Release 754551680Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551680ReactomeR-HSA-45516801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551680.1SUMO1:HERC2Reactome DB_ID: 4551752HERC2-SUMO1Small ubiquitin-related modifier 1SUMO1_HUMANReactome DB_ID: 455176197EQUAL2EQUAL97EQUALReactome Database ID Release 754551761Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551761ReactomeR-HSA-45517611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551761.11SUMO1-HERC2E3 ubiquitin-protein ligase HERC2 ecNumber6.3.2.-/ecNumberHERC2_HUMANReactome DB_ID: 45517581EQUAL4834EQUALReactome Database ID Release 754551758Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551758ReactomeR-HSA-45517581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551758.11Reactome Database ID Release 754551752Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551752ReactomeR-HSA-45517521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551752.1ACTIVATIONReactome Database ID Release 753215011Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3215011Reactome Database ID Release 754551724Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551724ReactomeR-HSA-45517242Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551724.222508508Pubmed2012DNA damage-inducible SUMOylation of HERC2 promotes RNF8 binding via a novel SUMO-binding Zinc fingerDanielsen, Jannie RendtlewPovlsen, Lou KlitgaardVillumsen, Bine HareStreicher, WernerNilsson, JakobWikström, MatsBekker-Jensen, SimonMailand, NielsJ. Cell Biol. 197:179-87LEFT-TO-RIGHTSUMOylation of MDC1 with SUMO1MDC1 is SUMOylated at lysine-1840 with SUMO1. SUMOyation of MDC1 is required for its degradation, which is thought to be directed by ubiquitinylation by RNF4 (Luo et al. 2012).Authored: May, B, 2013-09-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-19MDC1MDC1/NFBD1Reactome DB_ID: 75231UniProt:Q14676 MDC1MDC1KIAA0170NFBD1FUNCTION Required for checkpoint mediated cell cycle arrest in response to DNA damage within both the S phase and G2/M phases of the cell cycle. May serve as a scaffold for the recruitment of DNA repair and signal transduction proteins to discrete foci of DNA damage marked by 'Ser-139' phosphorylation of histone H2AX. Also required for downstream events subsequent to the recruitment of these proteins. These include phosphorylation and activation of the ATM, CHEK1 and CHEK2 kinases, and stabilization of TP53 and apoptosis. ATM and CHEK2 may also be activated independently by a parallel pathway mediated by TP53BP1.SUBUNIT Homodimer. Interacts with several proteins involved in the DNA damage response, although not all these interactions may be direct. Interacts with H2AX, which requires phosphorylation of H2AX on 'Ser-139'. Interacts with the MRN complex, composed of MRE11, RAD50, and NBN. Interacts with CHEK2, which requires ATM-mediated phosphorylation of 'Thr-68' within the FHA domain of CHEK2. Interacts constitutively with the BRCA1-BARD1 complex, SMC1A and TP53BP1. Interacts with ATM and FANCD2, and these interactions are reduced upon DNA damage. Also interacts with the PRKDC complex, composed of XRCC6/KU70, XRCC5/KU80 and PRKDC/XRCC7. This interaction may be required for PRKDC autophosphorylation, which is essential for DNA double strand break (DSB) repair. When phosphorylated by ATM, interacts with RNF8 (via FHA domain). Interacts with CEP164. When phosphorylated, interacts with APTX (via FHA-like domain).TISSUE SPECIFICITY Highly expressed in testis.DOMAIN Tandemly repeated BRCT domains are characteristic of proteins involved in DNA damage signaling. In MDC1, these repeats are required for localization to chromatin which flanks sites of DNA damage marked by 'Ser-139' phosphorylation of H2AX.PTM Phosphorylated upon exposure to ionizing radiation (IR), ultraviolet radiation (UV), and hydroxyurea (HU). Phosphorylation in response to IR requires ATM, NBN, and possibly CHEK2. Also phosphorylated during the G2/M phase of the cell cycle and during activation of the mitotic spindle checkpoint. Phosphorylation at Thr-4 by ATM stabilizes and enhances homodimerization via the FHA domain.PTM Sumoylation at Lys-1840 by PIAS4 following DNA damage promotes ubiquitin-mediated degradation.PTM Ubiquitinated by RNF4, leading to proteasomal degradation; undergoes 'Lys-48'-linked polyubiquitination.UniProtQ146761EQUAL2089EQUALReactome Database ID Release 7575231Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75231ReactomeR-HSA-752311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75231.1SUMO1:MDC1Reactome DB_ID: 4570497MDC1_HUMANSUMO1-K1840-MDC1Mediator of DNA damage checkpoint protein 1Reactome DB_ID: 45705461840EQUAL1EQUAL2089EQUALReactome Database ID Release 754570546Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570546ReactomeR-HSA-45705461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570546.11SUMO1_HUMANMDC1-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 457052797EQUAL2EQUAL97EQUALReactome Database ID Release 754570527Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570527ReactomeR-HSA-45705271Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570527.11Reactome Database ID Release 754570497Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570497ReactomeR-HSA-45704971Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570497.1ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 752997650Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2997650Reactome Database ID Release 754570554Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570554ReactomeR-HSA-45705542Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570554.222635276Pubmed2012Sumoylation of MDC1 is important for proper DNA damage responseLuo, KuntianZhang, HaoxingWang, LieweiYuan, JianLou, ZEMBO J. 31:3008-19LEFT-TO-RIGHTSUMOylation of MDC1 with SUMO2,3MDC1 is SUMOylated at lysine-1840 with SUMO2,3 (Luo et al. 2012, Hendriks et al. 2014, Tammsalu et al. 2014). SUMOylation is required for degradation of MDC1. SUMOylation of MDC1 is required for recruitment of RNF4 (Yin et al. 2012), which is believed to ubiquitinylate MDC1, resulting in degradation of MDC1.Authored: May, B, 2013-09-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-192MDC1_HUMANSUMO2,3-K1840-MDC1Mediator of DNA damage checkpoint protein 1Reactome DB_ID: 45704731840EQUAL1EQUAL2089EQUALReactome Database ID Release 754570473Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570473ReactomeR-HSA-45704731Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570473.1ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754570553Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570553ReactomeR-HSA-45705531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570553.124782567Pubmed2014Proteome-wide identification of SUMO2 modification sitesTammsalu, TriinMatic, IvanJaffray, Ellis GIbrahim, Adel F MTatham, Michael HHay, Ronald TSci Signal 7:rs222661230Pubmed2012SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damageYin, YiliSeifert, AnneChua, Joy ShijiaMaure, Jean-FrançoisGolebiowski, FilipHay, Ronald TGenes Dev. 26:1196-208LEFT-TO-RIGHTPIAS4 SUMOylates PARP1 with SUMO1PIAS4 SUMOylates PARP1 at lysine-203 and lysine-486 with SUMO1 (Martin et al. 2009, Matafora et al. 2009, Messner et al. 2009, Zilio et al. 2013, Impens et al. 2014). SUMOylation abrogates acetylation of PARP1 by p300 (Messner et al. 2009). PARP1 reciprocally poly(ADP-ribose)ylates PIAS4 (Martin et al. 2009). PARP1 is SUMOylated in response to heat shock and SUMOylation is required for full activation of the HSP70.1 promoter (Martin et al 2009).Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-13PARP1Poly (ADP-ribose) polymerase 1Reactome DB_ID: 201568UniProt:P09874 PARP1PARP1ADPRTPPOLFUNCTION Poly-ADP-ribosyltransferase that mediates poly-ADP-ribosylation of proteins and plays a key role in DNA repair (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272, PubMed:25043379, PubMed:26344098). Mainly mediates glutamate and aspartate ADP-ribosylation of target proteins: the ADP-D-ribosyl group of NAD(+) is transferred to the acceptor carboxyl group of glutamate and aspartate residues and further ADP-ribosyl groups are transferred to the 2'-position of the terminal adenosine moiety, building up a polymer with an average chain length of 20-30 units (PubMed:7852410, PubMed:9315851, PubMed:19764761, PubMed:25043379). Mediates the poly(ADP-ribosyl)ation of a number of proteins, including itself, APLF and CHFR (PubMed:17396150, PubMed:19764761). Also mediates serine ADP-ribosylation of target proteins following interaction with HPF1; HPF1 conferring serine specificity (PubMed:28190768). Probably also catalyzes tyrosine ADP-ribosylation of target proteins following interaction with HPF1 (PubMed:30257210). Catalyzes the poly-ADP-ribosylation of histones in a HPF1-dependent manner (PubMed:27067600). Involved in the base excision repair (BER) pathway by catalyzing the poly-ADP-ribosylation of a limited number of acceptor proteins involved in chromatin architecture and in DNA metabolism (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272). ADP-ribosylation follows DNA damage and appears as an obligatory step in a detection/signaling pathway leading to the reparation of DNA strand breaks (PubMed:17177976, PubMed:18172500, PubMed:19344625, PubMed:19661379, PubMed:23230272). In addition to base excision repair (BER) pathway, also involved in double-strand breaks (DSBs) repair: together with TIMELESS, accumulates at DNA damage sites and promotes homologous recombination repair by mediating poly-ADP-ribosylation (PubMed:26344098, PubMed:30356214). In addition to proteins, also able to ADP-ribosylate DNA: catalyzes ADP-ribosylation of DNA strand break termini containing terminal phosphates and a 2'-OH group in single- and double-stranded DNA, respectively (PubMed:27471034). Required for PARP9 and DTX3L recruitment to DNA damage sites (PubMed:23230272). PARP1-dependent PARP9-DTX3L-mediated ubiquitination promotes the rapid and specific recruitment of 53BP1/TP53BP1, UIMC1/RAP80, and BRCA1 to DNA damage sites (PubMed:23230272). Acts as a regulator of transcription: positively regulates the transcription of MTUS1 and negatively regulates the transcription of MTUS2/TIP150 (PubMed:19344625). Plays a role in the positive regulation of IFNG transcription in T-helper 1 cells as part of an IFNG promoter-binding complex with TXK and EEF1A1 (PubMed:17177976). Involved in the synthesis of ATP in the nucleus, together with NMNAT1, PARG and NUDT5 (PubMed:27257257). Nuclear ATP generation is required for extensive chromatin remodeling events that are energy-consuming (PubMed:27257257).SUBUNIT Homo- and heterodimer with PARP2. Interacts with APTX (PubMed:15044383). Component of a base excision repair (BER) complex, containing at least XRCC1, PARP1, PARP2, POLB and LRIG3 (By similarity). Interacts with SRY (PubMed:16904257). The SWAP complex consists of NPM1, NCL, PARP1 and SWAP70 (By similarity). Interacts with TIAM2 (By similarity). Interacts with PARP3; leading to activate PARP1 in absence of DNA (PubMed:20064938). Interacts (when poly-ADP-ribosylated) with CHD1L (PubMed:19661379). Interacts with the DNA polymerase alpha catalytic subunit POLA1; this interaction functions as part of the control of replication fork progression (PubMed:9518481). Interacts with EEF1A1 and TXK (PubMed:17177976). Interacts with RNF4 (PubMed:19779455). Interacts with RNF146 (PubMed:21799911). Interacts with ZNF423 (PubMed:22863007). Interacts with APLF (PubMed:17396150). Interacts with SNAI1 (via zinc fingers); the interaction requires SNAI1 to be poly-ADP-ribosylated and non-phosphorylated (active) by GSK3B (PubMed:21577210). Interacts (when poly-ADP-ribosylated) with PARP9 (PubMed:23230272). Interacts with NR4A3; activates PARP1 by improving acetylation of PARP1 and suppressing the interaction between PARP1 and SIRT1 (By similarity). Interacts (via catalytic domain) with PUM3; the interaction inhibits the poly-ADP-ribosylation activity of PARP1 and the degradation of PARP1 by CASP3 following genotoxic stress (PubMed:21266351). Interacts (via the PARP catalytic domain) with HPF1 (PubMed:27067600, PubMed:28190768). Interacts with ZNF365 (PubMed:23966166). Interacts with RRP1B (PubMed:19710015). Interacts with TIMELESS; the interaction is direct (PubMed:26344098). Interacts with CGAS; leading to impede the formation of the PARP1-TIMELESS complex (PubMed:30356214).PTM Phosphorylated by PRKDC (PubMed:10467406). Phosphorylated by TXK (PubMed:17177976).PTM Poly-ADP-ribosylated on glutamate and aspartate residues by autocatalysis (PubMed:19764761). Poly-ADP-ribosylated by PARP2; poly-ADP-ribosylation mediates the recruitment of CHD1L to DNA damage sites (PubMed:19661379). ADP-ribosylated on serine by autocatalysis; serine ADP-ribosylation takes place following interaction with HPF1 (PubMed:28190768).PTM S-nitrosylated, leading to inhibit transcription regulation activity.UniProtP098742EQUAL1014EQUALReactome Database ID Release 75201568Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=201568ReactomeR-HSA-2015681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-201568.122SUMO1:PARP1SUMO1:SUMO1:PARP1Reactome DB_ID: 4551687SUMO1_HUMANK203-PARP1-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 455162597EQUAL2EQUAL97EQUALReactome Database ID Release 754551625Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551625ReactomeR-HSA-45516251Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551625.11SUMO1_HUMANK486-PARP1-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 455174897EQUAL2EQUAL97EQUALReactome Database ID Release 754551748Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551748ReactomeR-HSA-45517481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551748.11SUMO1-K203,K486-PARP1Poly (ADP-ribose) polymerase 1Reactome DB_ID: 4551686203EQUAL486EQUAL2EQUAL1014EQUALReactome Database ID Release 754551686Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551686ReactomeR-HSA-45516861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551686.11Reactome Database ID Release 754551687Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551687ReactomeR-HSA-45516871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551687.12ACTIVATIONReactome Database ID Release 754551604Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551604ReactomeR-HSA-45516042Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551604.219596686Pubmed2009Proteomics analysis of nucleolar SUMO-1 target proteins upon proteasome inhibitionMatafora, VittoriaD'Amato, AlfonsinaMori, SilviaBlasi, FBachi, AngelaMol. Cell Proteomics 8:2243-5519622798Pubmed2009Sumoylation of poly(ADP-ribose) polymerase 1 inhibits its acetylation and restrains transcriptional coactivator functionMessner, SimonSchuermann, DavidAltmeyer, MatthiasKassner, IngridSchmidt, DarjaSchär, PrimoMüller, StefanHottiger, Michael OFASEB J. 23:3978-8925114211Pubmed2014Mapping of SUMO sites and analysis of SUMOylation changes induced by external stimuliImpens, FrancisRadoshevich, LillianaCossart, PascaleRibet, DavidProc. Natl. Acad. Sci. U.S.A. 111:12432-723871147Pubmed2013DNA-dependent SUMO modification of PARP-1Zilio, NicolaWilliamson, Chris TEustermann, SebastianShah, RajveeWest, Stephen CNeuhaus, DavidUlrich, Helle DDNA Repair (Amst.) 12:761-7319779455Pubmed2009PARP-1 transcriptional activity is regulated by sumoylation upon heat shockMartin, NadineSchwamborn, KlausSchreiber, ValérieWerner, AndreasGuillier, ChristelleZhang, Xiang-DongBischof, OliverSeeler, Jacob-SDejean, AnneEMBO J. 28:3534-48LEFT-TO-RIGHTPIAS4 SUMOylates PARP1 with SUMO2,3PIAS4 SUMOylates PARP1 at lysine-203 and lysine-486 with SUMO2,3 in response to heat shock (Martin et al. 2009, Lamoliatte et al. 2013, Hendriks et al. 2014, Tammsalu et al. 2014). PARP1 reciprocally poly(ADP-ribose)ylates PIAS4 (Martin et al. 2009). SUMOylation of PARP1 is required for full activation of the HSP70.1 promoter (Martin et al. 2009).Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-132SUMO2,3-K203,K486-PARP1Poly (ADP-ribose) polymerase 1Reactome DB_ID: 4551617203EQUAL486EQUAL2EQUAL1014EQUALReactome Database ID Release 754551617Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551617ReactomeR-HSA-45516172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551617.24ACTIVATIONReactome Database ID Release 754551768Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551768ReactomeR-HSA-45517682Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551768.223750026Pubmed2013Targeted identification of SUMOylation sites in human proteins using affinity enrichment and paralog-specific reporter ionsLamoliatte, FredericBonneil, EricDurette, ChantalCaron-Lizotte, OlivierWildemann, DirkZerweck, JohannesWenshuk, HolgerThibault, PierreMol. Cell Proteomics 12:2536-50LEFT-TO-RIGHTConjugation of SUMO1 to PMLUBE2I, HDAC7 SUMOylate PML with SUMO1UBE2I (UBC9) alone and in association with HDAC7 can SUMOylate PML with SUMO1 at lysine-65, lysine-160, and lysine-490 (Sternsdorf et al. 1997, Kamitani et al. 1998, Duprez et al. 1999, Knipscheer et al. 2008). SUMOylated PML is observed during interphase but not during mitosis (Everett et al. 1999). Knockdown of HDAC7 reduces the number of PML bodies (Gao et al. 2008).Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-23PMLProbable transcription factor PMLPML_HUMANReactome DB_ID: 1031706UniProt:P29590 PMLPMLMYLPP8675RNF71TRIM19FUNCTION Functions via its association with PML-nuclear bodies (PML-NBs) in a wide range of important cellular processes, including tumor suppression, transcriptional regulation, apoptosis, senescence, DNA damage response, and viral defense mechanisms. Acts as the scaffold of PML-NBs allowing other proteins to shuttle in and out, a process which is regulated by SUMO-mediated modifications and interactions. Isoform PML-4 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53/TP53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Isoform PML-4 also: acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2/E2F4 repressor complex, regulates double-strand break repair in gamma-irradiation-induced DNA damage responses via its interaction with WRN, acts as a negative regulator of telomerase by interacting with TERT, and regulates PER2 nuclear localization and circadian function. Isoform PML-6 inhibits specifically the activity of the tetrameric form of PKM. The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5) in concert with SATB1 are involved in local chromatin-loop remodeling and gene expression regulation at the MHC-I locus. Isoform PML-2 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Cytoplasmic PML is involved in the regulation of the TGF-beta signaling pathway. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration.FUNCTION Exhibits antiviral activity against both DNA and RNA viruses. The antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53/TP53 within these structures. Isoform PML-4 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs thereby preventing their nuclear egress and inhibiting formation of infectious virus particles. The sumoylated isoform PML-4 restricts rabies virus by inhibiting viral mRNA and protein synthesis. The cytoplasmic isoform PML-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. Isoform PML-6 shows restriction activity towards human cytomegalovirus (HCMV) and influenza A virus strains PR8(H1N1) and ST364(H3N2). Sumoylated isoform PML-4 and isoform PML-12 show antiviral activity against encephalomyocarditis virus (EMCV) by promoting nuclear sequestration of viral polymerase (P3D-POL) within PML NBs. Isoform PML-3 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells through the recruitment and the activation of p53/TP53 in the PML-NBs. Isoform PML-3 represses human foamy virus (HFV) transcription by complexing the HFV transactivator, bel1/tas, preventing its binding to viral DNA. PML may positively regulate infectious hepatitis C viral (HCV) production and isoform PML-2 may enhance adenovirus transcription.SUBUNIT Key component of PML bodies. PML bodies are formed by the interaction of PML homodimers (via SUMO-binding motif) with sumoylated PML, leading to the assembly of higher oligomers. Several types of PML bodies have been observed. PML bodies can form hollow spheres that can sequester target proteins inside. Interacts (via SUMO-binding motif) with sumoylated proteins. Interacts (via C-terminus) with p53/TP53. Recruits p53/TP53 and CHEK2 into PML bodies, which promotes p53/TP53 phosphorylation at 'Ser-20' and prevents its proteasomal degradation. Interacts with MDM2, and sequesters MDM2 in the nucleolus, thereby preventing ubiquitination of p53/TP53. Interaction with PML-RARA oncoprotein and certain viral proteins causes disassembly of PML bodies and abolishes the normal PML function. Interacts with HIPK2, TERT, SIRT1, TOPBP1, TRIM27 and TRIM69. Interacts with ELF4 (via C-terminus). Interacts with ITPR3. Interacts (in the cytoplasm) with TGFBR1, TGFBR2 and PKM. Interacts (via the coiled-coil domain and when sumoylated) with SATB1. Interacts with UBE2I; the interaction is enhanced by arsenic binding. Interacts (PML-RARA oncoprotein, via the coiled-coil domain) with UBE2I; the interaction is enhanced by arsenic binding and is required for PML-RARA oncoprotein sumoylation and inhibition of RARA transactivational activity. Interacts with RB1, PPP1A, SMAD2, SMAD3, DAXX, RPL11 and MTOR. Interacts with PPARGC1A and KAT2A. Interacts with CSNK2A1 and CSNK2A3. Interacts with ANKRD2; the interaction is direct. Interacts (via SUMO-interacting motif) with sumoylated MORC3 (PubMed:20501696). Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6 interact with RNF4. Isoform PML-1 interacts with NLRP3. Isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4 and isoform PML-5 interact with MAGEA2, RBL2, PER2 and E2F4. Isoform PML-2 interacts with CIITA. Isoform PML-2, isoform PML-3 and isoform PML-4 interact with TBX2. Isoform PML-4 interacts with RANBP2, HDAC7, KAT6A, WRN, PIN1, TBX3 and phosphorylated MAPK1/ERK2. Isoform PML-4 interacts with the CTNNB1 and TCF7L2/TCF4 complex. Isoform PML-4 preferentially interacts with MAPK7/BMK1 although other isoforms (isoform PML-1, isoform PML-2, isoform PML-3 and isoform PML-6) also interact with it. Isoform PML-12 interacts with PIAS1, PIAS2 (isoform PIAS2-alpha) and CSNK2A1/CK2. Interacts with TRIM16. Interacts with PRDM1/Blimp-1 (PubMed:28842558).SUBUNIT (Microbial infection) Interacts with Lassa virus Z protein and rabies virus phosphoprotein.SUBUNIT (Microbial infection) Isoform PML-1 interacts with herpes simplex virus-1/HHV-1 ICP0.SUBUNIT (Microbial infection) Isoform PML-2 interacts with human adenovirus 2 E1A and this interaction stimulates E1A-dependent transcriptional activation.SUBUNIT (Microbial infection) Isoform PML-4 interacts with VZV capsid protein VP26/ORF23 capsid protein.SUBUNIT (Microbial infection) The sumoylated isoform PML-4 interacts with encephalomyocarditis virus (EMCV) RNA-directed RNA polymerase 3D-POL (P3D-POL).SUBUNIT (Microbial infection) Isoform PML-6 interacts with moloney murine leukemia virus (MoMLV) integrase (IN) and reverse transcriptase (RT).SUBUNIT (Microbial infection) Isoform PML-4 and isoform PML-5 interact with human adenovirus 5 E1B-55K protein; these interactions promote efficient subnuclear targeting of E1B-55K to PML nuclear bodies.SUBUNIT (Microbial infection) Isoform PML-3 interacts with human foamy virus bel1/tas and bet.INDUCTION By interferons alpha, beta and gamma. Up-regulated by IRF3 and p53/TP53.DOMAIN The coiled-coil domain mediates a strong homo/multidimerization activity essential for core assembly of PML-NBs. Interacts with PKM via its coiled-coil domain (PubMed:18298799).DOMAIN The B box-type zinc binding domain and the coiled-coil domain mediate its interaction with PIAS1.DOMAIN Binds arsenic via the RING-type zinc finger. The RING-type zinc finger is essential for its interaction with HFV bel1/tas (PubMed:11432836).DOMAIN The unique C-terminal domains of isoform PML-2 and isoform PML-5 play an important role in regulating the localization, assembly dynamics, and functions of PML-NBs.DOMAIN The Sumo interaction motif (SIM) is required for efficient ubiquitination, recruitment of proteasome components within PML-NBs and PML degradation in response to arsenic trioxide.PTM Ubiquitinated; mediated by RNF4, RNF111, UHRF1, UBE3A/E6AP, BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex, SIAH1 or SIAH2 and leading to subsequent proteasomal degradation (PubMed:18408734, PubMed:21840486, PubMed:22033920). Ubiquitination by BCR(KLHL20) E3 ubiquitin ligase complex E3 ligase complex requires CDK1/2-mediated phosphorylation at Ser-518 which in turn is recognized by prolyl-isopeptidase PIN1 and PIN1-catalyzed isomerization further potentiates PML interaction with KLHL20 (PubMed:21840486, PubMed:22033920). 'Lys-6'-, 'Lys-11'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination by RNF4 is polysumoylation-dependent (PubMed:18408734). Ubiquitination by RNF111 is polysumoylation-dependent (By similarity).PTM Sumoylation regulates PML's: stability in response to extracellular or intracellular stimuli, transcription directly and indirectly, through sequestration of or dissociation of the transcription factors from PML-NBs, ability to regulate apoptosis and its anti-viral activities. It is also essential for: maintaining proper PML nuclear bodies (PML-NBs) structure and normal function, recruitment of components of PML-NBs, the turnover and retention of PML in PML-NBs and the integrity of PML-NBs. Undergoes 'Lys-11'-linked sumoylation. Sumoylation on all three sites (Lys-65, Lys-160 and Lys-490) is required for nuclear body formation. Sumoylation on Lys-160 is a prerequisite for sumoylation on Lys-65. Lys-65 and Lys-160 are sumoylated by PISA1 and PIAS2. PIAS1-mediated sumoylation of PML promotes its interaction with CSNK2A1/CK2 and phosphorylation at Ser-565 which in turn triggers its ubiquitin-mediated degradation. PIAS1-mediated sumoylation of PML-RARA promotes its ubiquitin-mediated degradation. The PML-RARA fusion protein requires the coiled-coil domain for sumoylation. Sumoylation at Lys-490 by RANBP2 is essential for the proper assembly of PML-NBs. SUMO1P1/SUMO5 conjugated PML at Lys-160, Lys-380, Lys-400, Lys-490 and Lys-497, but Lys-380, Lys-400 and Lys-497 are not key acceptor lysines. SUMO1P1/SUMO5 forms polymeric chain on Lys-160 of PML by successive conjugation at 'Lys-18'; facilitating recruitment of PML-NB components, which enlarges PML. SUMO1P1/SUMO5 conjugation of PML increases SUMO2/3 conjugation, which leads to the recruitment of RNF4 and ubiquitin-dependent disintegration of PML-NBs. SUMO1P1/SUMO5 monoconjugated Lys-490 (PubMed:27211601). DNA damage triggers its sumoylation while some but not all viral infections can abolish sumoylation. Desumoylated by SENP1, SENP2, SENP3, SENP5 and SENP6 (PubMed:27211601, PubMed:12419228, PubMed:21148299). Arsenic induces PML and PML-RARA polysumoylation and their subsequent RNF4-dependent ubiquitination and proteasomal degradation, and is used as treatment in acute promyelocytic leukemia (APL). The nuclear isoforms (isoform PML-1, isoform PML-2, isoform PML-3, isoform PML-4, isoform PML-5 and isoform PML-6) show an increased sumoylation in response to arsenic trioxide. The cytoplasmic isoform PML-7 is not sumoylated.PTM Phosphorylation is a major regulatory mechanism that controls PML protein abundance and the number and size of PML nuclear bodies (PML-NBs). Phosphorylated in response to DNA damage, probably by ATR. HIPK2-mediated phosphorylation at Ser-8, Ser-36 and Ser-38 leads to increased accumulation of PML protein and its sumoylation and is required for the maximal pro-apoptotic activity of PML after DNA damage. CHEK2-mediated phosphorylation at Ser-117 is important for PML-mediated apoptosis following DNA damage. MAPK1-mediated phosphorylations at Ser-403, Ser-505, Ser-527 and Ser-530 and CDK1/2-mediated phosphorylation at Ser-518 promote PIN1-dependent PML degradation. CK2-mediated phosphorylation at Ser-565 primes PML ubiquitination via an unidentified ubiquitin ligase.PTM Acetylation at Lys-487 is essential for its nuclear localization. Deacetylated at Lys-487 by SIRT1 and this deacetylation promotes PML control of PER2 nuclear localization.DISEASE A chromosomal aberration involving PML may be a cause of acute promyelocytic leukemia (APL). Translocation t(15;17)(q21;q21) with RARA. The PML breakpoints (type A and type B) lie on either side of an alternatively spliced exon.UniProtP295901EQUAL882EQUALReactome Database ID Release 751031706Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1031706ReactomeR-HSA-10317062Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1031706.233SUMO1:PMLSUMO1:SUMO1:SUMO1:PMLReactome DB_ID: 3730883SUMO1_HUMANK65-PML-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 373087997EQUAL2EQUAL97EQUALReactome Database ID Release 753730879Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730879ReactomeR-HSA-37308791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730879.11PML_HUMANSUMO1-K65,160,490-PMLSUMO1 N-glycyl-lys65,160,490 PMLProtein PMLReactome DB_ID: 300044065EQUAL160EQUAL490EQUAL1EQUAL882EQUALReactome Database ID Release 753000440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000440ReactomeR-HSA-30004401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000440.11SUMO1_HUMANK490-PML-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 373083397EQUAL2EQUAL97EQUALReactome Database ID Release 753730833Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730833ReactomeR-HSA-37308331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730833.11SUMO1_HUMANK160-PML-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 373088497EQUAL2EQUAL97EQUALReactome Database ID Release 753730884Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730884ReactomeR-HSA-37308841Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730884.11Reactome Database ID Release 753730883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730883ReactomeR-HSA-37308831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730883.13ACTIVATIONConverted from EntitySet in ReactomeUBE2I,HDAC7Reactome DB_ID: 3000385HDAC7Histone deacetylase 7HDAC7_HUMANReactome DB_ID: 3004534UniProt:Q8WUI4 HDAC7HDAC7HDAC7AFUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).SUBUNIT Interacts with HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, NCOR1, NCOR2, SIN3A, SIN3B, RBBP4, RBBP7, MTA1L1, SAP30 and MBD3. Interacts with the 14-3-3 protein YWHAE, MEF2A, MEF2B and MEF2C (By similarity). Interacts with KAT5 and EDNRA. Interacts with KDM5B. Interacts with ZMYND15 (By similarity). Interacts with PML (isoform PML-4). Interacts with FOXP3. Interacts with RARA (PubMed:28167758).DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.PTM May be phosphorylated by CaMK1. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylation at Ser-155 by MARK2, MARK3 and PRKD1 promotes interaction with 14-3-3 proteins and export from the nucleus. Phosphorylation at Ser-155 is a prerequisite for phosphorylation at Ser-181.MISCELLANEOUS Its activity is inhibited by Trichostatin A (TSA), a known histone deacetylase inhibitor.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily.UniProtQ8WUI41EQUAL952EQUALReactome Database ID Release 753004534Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3004534ReactomeR-HSA-30045341Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3004534.1Reactome Database ID Release 753000385Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000385ReactomeR-HSA-30003851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000385.1Reactome Database ID Release 753000356Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000356Reactome Database ID Release 753000383Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000383ReactomeR-HSA-30003831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000383.19452416Pubmed1998Covalent modification of PML by the sentrin family of ubiquitin-like proteinsKamitani, TNguyen, H PKito, KFukuda-Kamitani, TYeh, E TJ. Biol. Chem. 273:3117-209412458Pubmed1997Evidence for covalent modification of the nuclear dot-associated proteins PML and Sp100 by PIC1/SUMO-1Sternsdorf, TJensen, KWill, HJ. Cell Biol. 139:1621-3418625722Pubmed2008Histone deacetylase 7 promotes PML sumoylation and is essential for PML nuclear body formationGao, ChengzhuoHo, Chun-ChenReineke, ErinLam, MinhCheng, XiwenStanya, Kristopher JLiu, YuChakraborty, SharmisthaShih, Hsiu-MingKao, HYMol. Cell. Biol. 28:5658-679885291Pubmed1999SUMO-1 modification of the acute promyelocytic leukaemia protein PML: implications for nuclear localisationDuprez, ESaurin, A JDesterro, J MLallemand-Breitenbach, VHowe, KBoddy, M NSolomon, Ede Thé, HHay, R TFreemont, P SJ. Cell. Sci. 112:381-9310574707Pubmed1999Cell cycle regulation of PML modification and ND10 compositionEverett, R DLomonte, PSternsdorf, Tvan Driel, ROrr, AJ. Cell. Sci. 112:4581-89756909Pubmed1998Identification of three major sentrinization sites in PMLKamitani, TKito, KNguyen, H PWada, HFukuda-Kamitani, TYeh, E TJ. Biol. Chem. 273:26675-8218691969Pubmed2008Ubc9 sumoylation regulates SUMO target discriminationKnipscheer, PuckFlotho, AnnetteKlug, HeleneOlsen, Jesper Vvan Dijk, Willem JFish, AlexanderJohnson, Erica SMann, MatthiasSixma, Titia KPichler, AndreaMol. Cell 31:371-8221098080Pubmed2011A novel proteomics approach to identify SUMOylated proteins and their modification sites in human cellsGalisson, FredericMahrouche, LouizaCourcelles, MathieuBonneil, EricMeloche, SylvainChelbi-Alix, Mounira KThibault, PierreMol. Cell Proteomics 10:M110.004796LEFT-TO-RIGHTRANBP2 SUMOylates PML with SUMO1RANBP2 of the nuclear pore complex SUMOylates PML with SUMO1 at lysine-65, lysine-160, and lysine-490 (Sternsdorf et al. 1997, Kamitani et al. 1998, Duprez et al. 1999). SUMOylated PML is observed during interphase but not during mitosis (Everett et al. 1999). RANBP2 contains both a binding site for SUMO1 and a binding site for UBE2I (Tatham et al. 2005). The binding site for SUMO1 may play a role in SUMOylation of PML with SUMO1. Knockdown of RANBP2 reduces the number of PML bodies (Saitoh et al. 2006).Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-2333ACTIVATIONactiveUnit: #Protein107Nuclear Pore Complex (NPC)Reactome DB_ID: 157689nuclear envelopeGENE ONTOLOGYGO:0005635NUP153Nup153Reactome DB_ID: 157695UniProt:P49790 NUP153NUP153FUNCTION Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with TPR, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Mediates TPR anchoring to the nuclear membrane at NPC. The repeat-containing domain may be involved in anchoring other components of the NPC to the pore membrane. Possible DNA-binding subunit of the nuclear pore complex (NPC).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and thereby promotes the integration of the virus in the nucleus of non-dividing cells (in vitro).FUNCTION (Microbial infection) Binds HIV-2 protein vpx and thereby promotes the nuclear translocation of the lentiviral genome (in vitro).SUBUNIT Interacts with RAN; the interaction occurs in a GTP- and GDP-independent manner (By similarity). Part of the nuclear pore complex (NPC). Interacts with TPR (via coiled coil region); the interaction is direct and provides a link between the core structure and the TPR-containing nuclear basket of the nuclear pore complex (NPC). Interacts with HIKESHI, SENP2 and XPO5. Interacts with MCM3AP isoform GANP; this interaction is required for GANP localization at the nuclear pore complex (PubMed:20005110, PubMed:23652018).SUBUNIT (Microbial infection) Interacts (via C-terminus) with HIV-1 capsid protein p24 (CA) (via N-terminus).SUBUNIT (Microbial infection) Interacts with HIV-1 integrase; this interaction might play a role in nuclear import of HIV pre-integration complex.SUBUNIT (Microbial infection) Interacts with hepatitis B virus capsid protein; this interaction probably plays a role in nuclear import of HBV genome.SUBUNIT (Microbial infection) Interacts with Epstein-barr virus BGLF4; this interaction allows BGLF4 nuclear entry.SUBUNIT (Microbial infection) Interacts with HIV-2 virus protein vpx; this interaction might promote vpx nuclear entry.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN (Microbial infection) FG repeats mediates interaction with HIV-1 capsid protein p24 (CA).PTM Phosphorylated in interphase, hyperphosphorylated during mitosis. May play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.PTM O-glycosylated during cytokinesis at sites identical or close to phosphorylation sites, this interferes with the phosphorylation status.SIMILARITY Belongs to the NUP153 family.UniProtP497902EQUAL1475EQUALReactome Database ID Release 75157695Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157695ReactomeR-HSA-1576951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157695.18NUP214Nup214Reactome DB_ID: 157691cytosolGENE ONTOLOGYGO:0005829UniProt:P35658 NUP214NUP214CAINCANKIAA0023FUNCTION Part of the nuclear pore complex (PubMed:9049309). Has a critical role in nucleocytoplasmic transport (PubMed:31178128). May serve as a docking site in the receptor-mediated import of substrates across the nuclear pore complex (PubMed:31178128, PubMed:8108440).FUNCTION (Microbial infection) Required for capsid disassembly of the human adenovirus 5 (HadV-5) leading to release of the viral genome to the nucleus (in vitro).SUBUNIT Homodimer. Part of the nuclear pore complex (NPC) (PubMed:9049309). Interacts with NUP88 (PubMed:9049309, PubMed:30543681). Interacts with ZFP36; this interaction increases upon lipopolysaccharide (LPS) stimulation (PubMed:14766228). Interacts with DDX19 (PubMed:19219046, PubMed:19208808). Interacts with XPO1 (PubMed:9049309). Interacts with XPO5 (PubMed:11777942).SUBUNIT (Microbial infection) Interacts with human herpes virus 1 (HHV-1) protein UL25; this interaction might be essential to the capsid docking onto the host nuclear pore.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 (HAdV-5) protein L3 (hexon); this interaction might be essential for the release of the virus genome to the nucleus.TISSUE SPECIFICITY Expressed in thymus, spleen, bone marrow, kidney, brain and testis, but hardly in all other tissues or in whole embryos during development.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN The beta-propeller contains long interblade connector loops, and mediates interaction with DDX19B.PTM Probably glycosylated as it reacts with wheat germ agglutinin (WGA).DISEASE A chromosomal aberration involving NUP214 is found in a subset of acute myeloid leukemia (AML); also known as acute non-lymphocytic leukemia. Translocation t(6;9)(p23;q34) with DEK. It results in the formation of a DEK-CAN fusion gene.DISEASE A chromosomal aberration involving NUP214 is found in some cases of acute undifferentiated leukemia (AUL). Translocation t(6;9)(q21;q34.1) with SET.DISEASE Chromosomal aberrations involving NUP214 are found in acute lymphoblastic leukemia (PubMed:20851865, PubMed:15361874). Translocation t(9;9)(q34;q34) with ABL1 (PubMed:15361874). Translocation t(5;9)(q35;q34) with SQSTM1 (PubMed:20851865).UniProtP356581EQUAL2090EQUALReactome Database ID Release 75157691Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157691ReactomeR-HSA-1576911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157691.18Seh1SEH1L-2Reactome DB_ID: 157750UniProt:Q96EE3-2 SEH1LSEH1LSEC13LSEH1FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).SIMILARITY Belongs to the WD repeat SEC13 family.UniProt IsoformQ96EE3-21EQUAL360EQUALReactome Database ID Release 75157750Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157750ReactomeR-HSA-1577501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157750.116Nup107-160 complexReactome DB_ID: 377883NUP107Nup107Reactome DB_ID: 376241UniProt:P57740 NUP107NUP107FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:12552102, PubMed:15229283, PubMed:30179222). Required for the assembly of peripheral proteins into the NPC (PubMed:15229283, PubMed:12552102). May anchor NUP62 to the NPC (PubMed:15229283). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:12802065, PubMed:15229283, PubMed:26411495). Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96; this complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705, PubMed:26411495, PubMed:30179222). Does not interact with TPR (PubMed:12802065). Interacts with ZNF106 (By similarity).TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.SIMILARITY Belongs to the nucleoporin Nup84/Nup107 family.UniProtP577401EQUAL925EQUALReactome Database ID Release 75376241Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376241ReactomeR-HSA-3762411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376241.11NUP160Nup160Reactome DB_ID: 376253UniProt:Q12769 NUP160NUP160KIAA0197NUP120FUNCTION Functions as a component of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Involved in poly(A)+ RNA transport.SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:11564755, PubMed:11684705). Forms part of the NUP160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96 (PubMed:11564755, PubMed:11684705). This complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11564755, PubMed:11684705).CAUTION It is uncertain whether Met-1 or Met-35 is the initiator.UniProtQ127691EQUAL1436EQUALReactome Database ID Release 75376253Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376253ReactomeR-HSA-3762531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376253.11Nup96NUP98-5NUP98 isoform 5Reactome DB_ID: 376247UniProt:P52948-5 NUP98NUP98ADAR2FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change ASN-74-ASP is reduced (in vitro) (PubMed:23523133).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).SUBUNIT (Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).DOMAIN Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.PTM Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.DISEASE Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).DISEASE A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.DISEASE Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.DISEASE A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.DISEASE A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.DISEASE A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.SIMILARITY Belongs to the nucleoporin GLFG family.UniProt IsoformP52948-51EQUAL880EQUALReactome Database ID Release 75376247Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376247ReactomeR-HSA-3762472Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376247.21NUP133Nup133Reactome DB_ID: 376251UniProt:Q8WUM0 NUP133NUP133FUNCTION Involved in poly(A)+ RNA transport. Involved in nephrogenesis (PubMed:30179222).SUBUNIT Forms part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and Nup96. This complex plays a role in RNA export and in tethering Nup98 and NUP153 to the nucleus.TISSUE SPECIFICITY Widely expressed in fetal and adult tissues. Expressed in the brain and kidney.SIMILARITY Belongs to the nucleoporin Nup133 family.UniProtQ8WUM01EQUAL1156EQUALReactome Database ID Release 75376251Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376251ReactomeR-HSA-3762511Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376251.11SEC13SEC13-related proteinSC13_HUMANReactome DB_ID: 203981UniProt:P55735 SEC13SEC13D3S1231ESEC13ASEC13L1SEC13RFUNCTION Functions as a component of the nuclear pore complex (NPC) and the COPII coat. At the endoplasmic reticulum, SEC13 is involved in the biogenesis of COPII-coated vesicles (PubMed:8972206). Required for the exit of adipsin (CFD/ADN), an adipocyte-secreted protein from the endoplasmic reticulum (By similarity).FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT At the nuclear pore: component of the Y-shaped Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. At the COPII coat complex: interacts with SEC31A and SEC31B. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:14517296, PubMed:16495487, PubMed:16957052, PubMed:18160040, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612). Interacts with SEC16A (PubMed:17428803, PubMed:19638414, PubMed:25201882). Interacts with SEC16B (PubMed:22355596).SIMILARITY Belongs to the WD repeat SEC13 family.UniProtP557352EQUAL322EQUALReactome Database ID Release 75203981Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=203981ReactomeR-HSA-2039811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-203981.11SEH1L-1SEH1L isoform 1Reactome DB_ID: 376246UniProt:Q96EE3-1 SEH1LSEH1LSEC13LSEH1FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. This subunit plays a role in recruitment of the Nup107-160 subcomplex to the kinetochore.FUNCTION As a component of the GATOR subcomplex GATOR2, functions within the amino acid-sensing branch of the TORC1 signaling pathway. Indirectly activates mTORC1 and the TORC1 signaling pathway through the inhibition of the GATOR1 subcomplex (PubMed:23723238). It is negatively regulated by the upstream amino acid sensors SESN2 and CASTOR1 (PubMed:25457612, PubMed:27487210).SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13. The SEH1 subunit appears to be only weakly associated with the Nup107-160 subcomplex. Within the GATOR complex, component of the GATOR2 subcomplex, made of MIOS, SEC13, SEH1L, WDR24 and WDR59. The GATOR complex strongly interacts with RRAGA/RRAGC and RRAGB/RRAGC heterodimers (PubMed:17360435, PubMed:23723238). The GATOR2 complex interacts with CASTOR2 and CASTOR1; the interaction is negatively regulated by arginine (PubMed:26972053). The GATOR2 complex interacts with SESN1, SESN2 and SESN3; the interaction is negatively regulated by amino acids (PubMed:25263562, PubMed:25457612).SIMILARITY Belongs to the WD repeat SEC13 family.UniProt IsoformQ96EE3-11EQUAL360EQUALReactome Database ID Release 75376246Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376246ReactomeR-HSA-3762461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376246.11NUP43Nup43Reactome DB_ID: 376243UniProt:Q8NFH3 NUP43NUP43FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13.UniProtQ8NFH31EQUAL380EQUALReactome Database ID Release 75376243Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376243ReactomeR-HSA-3762431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376243.11NUP85Nup85Reactome DB_ID: 376238UniProt:Q9BW27 NUP85NUP85NUP75PCNT1FUNCTION Essential component of the nuclear pore complex (NPC) that seems to be required for NPC assembly and maintenance (PubMed:12718872). As part of the NPC Nup107-160 subcomplex plays a role in RNA export and in tethering NUP96/Nup98 and NUP153 to the nucleus (PubMed:12718872). The Nup107-160 complex seems to be required for spindle assembly during mitosis (PubMed:16807356). NUP85 is required for membrane clustering of CCL2-activated CCR2 (PubMed:15995708). Seems to be involved in CCR2-mediated chemotaxis of monocytes and may link activated CCR2 to the phosphatidyl-inositol 3-kinase-Rac-lammellipodium protrusion cascade (PubMed:15995708). Involved in nephrogenesis (PubMed:30179222).SUBUNIT Component of the nuclear pore complex (NPC) (PubMed:12196509). Component of the NPC Nup107-160 subcomplex, consisting of at least NUP107, NUP98/Nup96, NUP160, NUP133, NUP85, NUP37, NUP43 and SEC13 (PubMed:15146057). Interacts with NUP160, NUP133 and SEC13 (PubMed:12718872, PubMed:30179222). Interacts with NUP37, NUP107 and NUP43 (PubMed:15146057). Interacts with CCR2 (PubMed:15995708).SIMILARITY Belongs to the nucleoporin Nup85 family.UniProtQ9BW271EQUAL656EQUALReactome Database ID Release 75376238Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376238ReactomeR-HSA-3762381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376238.11NUP37Nup37Reactome DB_ID: 376237UniProt:Q8NFH4 NUP37NUP37FUNCTION Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex is required for the assembly of a functional NPC. The Nup107-160 subcomplex is also required for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation.SUBUNIT Component of the Nup107-160 subcomplex of the nuclear pore complex (NPC). The Nup107-160 subcomplex includes NUP160, NUP133, NUP107, NUP98, NUP85, NUP43, NUP37, SEH1 and SEC13.UniProtQ8NFH41EQUAL326EQUALReactome Database ID Release 75376237Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=376237ReactomeR-HSA-3762371Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-376237.11Reactome Database ID Release 75377883Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=377883ReactomeR-HSA-3778832Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-377883.232NUPL2NLP1/CG1Reactome DB_ID: 157697UniProt:O15504 NUP42NUP42CG1NUPL2FUNCTION Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm.FUNCTION (Microbial infection) In case of infection by HIV-1, it may participate in the docking of viral Vpr at the nuclear envelope.SUBUNIT Probable component of the nuclear pore complex (NPC). Interacts with nuclear export protein NXF1 (PubMed:10228171). Interacts with GLE1. Able to form a heterotrimer with NUP155 and GLE1 in vitro (PubMed:16000379). Interacts with XPO1 (PubMed:10358091).SUBUNIT (Microbial infection) Interacts with the HIV-1 virus proteins Rev and Vpr. The interaction with HIV-1 Rev, a protein that mediates nuclear export of unspliced viral RNAs, suggests that its function may be bypassed by the HIV-1 virus.TISSUE SPECIFICITY Ubiquitously expressed.DOMAIN The FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC.PTM O-glycosylated.UniProtO155041EQUAL423EQUALReactome Database ID Release 75157697Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157697ReactomeR-HSA-1576971Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157697.116RANBP2Nup358Reactome DB_ID: 157703UniProt:P49792 RANBP2RANBP2NUP358FUNCTION E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I (PubMed:11792325, PubMed:12032081, PubMed:15378033, PubMed:22194619, PubMed:15931224). Involved in transport factor (Ran-GTP, karyopherin)-mediated protein import via the F-G repeat-containing domain which acts as a docking site for substrates (PubMed:7775481). Binds single-stranded RNA (in vitro) (PubMed:7775481). May bind DNA (PubMed:7775481). Component of the nuclear export pathway (PubMed:10078529). Specific docking site for the nuclear export factor exportin-1 (PubMed:10078529). Sumoylates PML at 'Lys-490' which is essential for the proper assembly of PML-NB (PubMed:22155184). Recruits BICD2 to the nuclear envelope and cytoplasmic stacks of nuclear pore complex known as annulate lamellae during G2 phase of cell cycle (PubMed:20386726). Probable inactive PPIase with no peptidyl-prolyl cis-trans isomerase activity (PubMed:20676357, PubMed:23353830).PATHWAY Protein modification; protein sumoylation.SUBUNIT Part of the nuclear pore complex (PubMed:11839768, PubMed:20386726, PubMed:23353830, PubMed:7603572). Forms a complex with NXT1, NXF1 and RANGAP1 (PubMed:14729961). Forms a tight complex with RANBP1 and UBE2I (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with SUMO1 but not SUMO2 (PubMed:15388847, PubMed:10078529, PubMed:15826666). Interacts with PRKN (PubMed:16332688). Interacts with sumoylated RANGAP1 (PubMed:15378033, PubMed:10078529, PubMed:15826666). Interacts with CDCA8 (PubMed:19413330). Interacts with PML (isoform PML-4) (PubMed:22155184). Interacts with BICD2 (PubMed:20386726). Interacts with MCM3AP isoform GANP (PubMed:20005110).DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.DOMAIN The PPIase cyclophilin-type domain has high structural similarity with PPIA, but has extremely low and barely detectable proline isomerase activity (in vitro) (PubMed:23353830). Only about half of the residues that surround the PPIA active site cleft are conserved.PTM Polyubiquitinated by PRKN, which leads to proteasomal degradation.PTM The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.DISEASE A chromosomal aberration involving RANBP2 is a cause of chromosome 8p11 myeloproliferative syndrome. Translocation t(2;8)(q12;p11) with FGFR1. Chromosome 8p11 myeloproliferative syndrome is characterized by myeloid hyperplasia, eosinophilia and T-cell or B-cell lymphoblastic lymphoma. In general it progresses to acute myeloid leukemia.SIMILARITY Belongs to the RanBP2 E3 ligase family.CAUTION Despite the presence of a PPIase cyclophilin-type domain, it has probably no peptidyl-prolyl cis-trans isomerase activity.UniProtP497921EQUAL3224EQUALReactome Database ID Release 75157703Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157703ReactomeR-HSA-1577031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157703.18NUP88Nup88Reactome DB_ID: 157753UniProt:Q99567 NUP88NUP88FUNCTION Component of nuclear pore complex.SUBUNIT Interacts with NUP214/CAN (PubMed:9049309, PubMed:30543681). Interacts with NUP62 and NUP98 (PubMed:30543681).TISSUE SPECIFICITY Ubiquitous.UniProtQ995671EQUAL741EQUALReactome Database ID Release 75157753Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157753ReactomeR-HSA-1577531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157753.132TPRTprReactome DB_ID: 157692UniProt:P12270 TPRTPRFUNCTION Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Functions as a scaffolding element in the nuclear phase of the NPC essential for normal nucleocytoplasmic transport of proteins and mRNAs, plays a role in the establishment of nuclear-peripheral chromatin compartmentalization in interphase, and in the mitotic spindle checkpoint signaling during mitosis. Involved in the quality control and retention of unspliced mRNAs in the nucleus; in association with NUP153, regulates the nuclear export of unspliced mRNA species bearing constitutive transport element (CTE) in a NXF1- and KHDRBS1-independent manner. Negatively regulates both the association of CTE-containing mRNA with large polyribosomes and translation initiation. Does not play any role in Rev response element (RRE)-mediated export of unspliced mRNAs. Implicated in nuclear export of mRNAs transcribed from heat shock gene promoters; associates both with chromatin in the HSP70 promoter and with mRNAs transcribed from this promoter under stress-induced conditions. Modulates the nucleocytoplasmic transport of activated MAPK1/ERK2 and huntingtin/HTT and may serve as a docking site for the XPO1/CRM1-mediated nuclear export complex. According to some authors, plays a limited role in the regulation of nuclear protein export (PubMed:22253824 and PubMed:11952838). Plays also a role as a structural and functional element of the perinuclear chromatin distribution; involved in the formation and/or maintenance of NPC-associated perinuclear heterochromatin exclusion zones (HEZs). Finally, acts as a spatial regulator of the spindle-assembly checkpoint (SAC) response ensuring a timely and effective recruitment of spindle checkpoint proteins like MAD1L1 and MAD2L1 to unattached kinetochore during the metaphase-anaphase transition before chromosome congression. Its N-terminus is involved in activation of oncogenic kinases.SUBUNIT Interacts with IFI204 (via C-terminal region). Interacts with IFI203 (By similarity). Homodimer. Part of the nuclear pore complex (NPC). Associates with the XPO1/CRM1-mediated nuclear export complex, the Importin alpha/Importin beta receptor and the dynein 1 complex. Interacts (via C-terminal domain) with the KPNB1; the interaction occurs in a RanGTP-dependent manner. Interacts (via C-terminal regionand phosphorylated form) with MAPK1/ERK2 (via phosphorylated form); the interaction requires dimerization of MAPK1/ERK2 and increases following EGF stimulation. Interacts with MAPK3/ERK1; the interaction increases following EGF stimulation. Interacts (via coiled coil region) with NUP153; the interaction is direct. Interacts with HSF1; the interaction increases in a stress-responsive manner and stimulates export of stress-induced HSP70 mRNA. Interacts with huntingtin/HTT; the interaction is inhibited by aggregated huntingtin/HTT forms with expanded polyglutamine stretch. Interacts with MAD1L1 (via N-terminal region), MAD2L1, and TTK; the interactions occurs in a microtubule-independent manner. Interacts (via middle region) with DYNLL1. Interacts with DCTN1, dynein, NUP153 and tubulin. Interacts with MTA1.TISSUE SPECIFICITY Expressed in esophagus, ovary, liver, skin, smooth muscles, cerebrum and fetal cerebellum (at protein level). Highest in testis, lung, thymus, spleen and brain, lower levels in heart, liver and kidney.DOMAIN The N-terminal domain mediates intranuclear attachment to the nuclear pore complex. The C-terminal domain mediates its nuclear import.PTM Phosphorylated. Phosphorylation occurs on serine and threonine residues (comprised in the C-terminal region) by MAPK1/ERK2 and stabilizes the interaction between these two proteins.PTM Proteolytically degraded after poliovirus (PV) infection; degradation is restricted to its unfolded C-terminal tail domain whereas its coiled-coil domain containing NCP- and NUP153-binding domains withstand degradation.DISEASE A chromosomal aberration involving TPR has been found in papillary thyroid carcinomas (PTCs). Intrachromosomal rearrangement that links the 5'-end of the TPR gene to the protein kinase domain of NTRK1 forms the fusion protein TRK-T1. TRK-T1 is a 55 kDa protein reacting with antibodies against the carboxy terminus of the NTRK1 protein.DISEASE Involved in tumorigenic rearrangements with the MET.SIMILARITY Belongs to the TPR family.UniProtP122702EQUAL2363EQUALReactome Database ID Release 75157692Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157692ReactomeR-HSA-1576921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157692.116Gp210NUP210Reactome DB_ID: 157722UniProt:Q8TEM1 NUP210NUP210KIAA0906PSEC0245FUNCTION Nucleoporin essential for nuclear pore assembly and fusion, nuclear pore spacing, as well as structural integrity.SUBUNIT Forms dimers and possibly higher-order oligomers.TISSUE SPECIFICITY Ubiquitous expression, with highest levels in lung, liver, pancreas, testis, and ovary, intermediate levels in brain, kidney, and spleen, and lowest levels in heart and skeletal muscle.PTM N-glycosylated, but not all potential glycosylation sites may be used. Contains high-mannose type oligosaccharides (By similarity).PTM Phosphorylated at Ser-1881 in mitosis specifically; not phosphorylated in interphase.MISCELLANEOUS Recognized by antinuclear autoantibodies in primary biliary cirrhosis.MISCELLANEOUS Knockdown of NUP210 causes nuclear membranes to accumulate aberrant structures termed twinned and fusion-arrested membranes and nuclear pore complex to cluster. Induces cell death and chromatin disruptions.SIMILARITY Belongs to the NUP210 family.UniProtQ8TEM127EQUAL1887EQUALReactome Database ID Release 75157722Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157722ReactomeR-HSA-1577221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157722.116NUP50Nup50Reactome DB_ID: 157740UniProt:Q9UKX7 NUP50NUP50NPAP60LPRO1146FUNCTION Component of the nuclear pore complex that has a direct role in nuclear protein import (PubMed:20016008). Actively displaces NLSs from importin-alpha, and facilitates disassembly of the importin-alpha:beta-cargo complex and importin recycling (PubMed:20016008). Interacts with regulatory proteins of cell cycle progression including CDKN1B (By similarity). This interaction is required for correct intracellular transport and degradation of CDKN1B (By similarity).SUBUNIT Interacts with Importin alpha-2, Importin beta, Importin beta-2, NUP153, Ran binding protein 7, CDKN1B and itself (By similarity). Does not interact with TPR.TISSUE SPECIFICITY Ubiquitous. Highest levels in testis, peripheral blood leukocytes and fetal liver.DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.UniProtQ9UKX71EQUAL468EQUALReactome Database ID Release 75157740Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157740ReactomeR-HSA-1577401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157740.132Nup93 complexReactome DB_ID: 9634183NUP155Nup155Reactome DB_ID: 157690UniProt:O75694 NUP155NUP155KIAA0791FUNCTION Essential component of nuclear pore complex. Could be essessential for embryogenesis. Nucleoporins may be involved both in binding and translocating proteins during nucleocytoplasmic transport.SUBUNIT Interacts with GLE1. Able to form a heterotrimer with GLE1 and NUP42 in vitro. Forms a complex with NUP35, NUP93, NUP205 and lamin B.TISSUE SPECIFICITY Expressed in all tissues tested, including heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.PTM Phosphorylated. Phosphorylation and dephosphorylation may be important for the function of NUP155 and may play a role in the reversible disassembly of the nuclear pore complex during mitosis (By similarity).PTM Disulfide-linked to NUP62. The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC (By similarity).SIMILARITY Belongs to the non-repetitive/WGA-negative nucleoporin family.UniProtO756941EQUAL1391EQUALReactome Database ID Release 75157690Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157690ReactomeR-HSA-1576901Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157690.11NUP93Nup93Reactome DB_ID: 157749UniProt:Q8N1F7 NUP93NUP93KIAA0095FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor nucleoporins, but not NUP153 and TPR, to the NPC. During renal development, regulates podocyte migration and proliferation through SMAD4 signaling (PubMed:26878725).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283, PubMed:15703211). Component of the p62 complex, a complex composed of NUP62 and NUP54 (PubMed:9348540). Forms a complex with NUP35, NUP155, NUP205 and lamin B; the interaction with NUP35 is direct (PubMed:15703211). Does not interact with TPR (PubMed:12802065, PubMed:15229283). Interacts with SMAD4 and IPO7; translocates SMAD4 to the nucleus through the NPC upon BMP7 stimulation resulting in activation of SMAD4 signaling (PubMed:26878725).SUBUNIT (Microbial infection) Interacts with SARS-CoV translation inhibitor nsp1; this interaction may disrupt nuclear pore function.SIMILARITY Belongs to the nucleoporin interacting component (NIC) family.UniProtQ8N1F71EQUAL819EQUALReactome Database ID Release 75157749Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157749ReactomeR-HSA-1577491Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157749.11MP44NUP35Nup35NUP53Reactome DB_ID: 157748UniProt:Q8NFH5 NUP35NUP35MP44NUP53FUNCTION Functions as a component of the nuclear pore complex (NPC). NPC components, collectively referred to as nucleoporins (NUPs), can play the role of both NPC structural components and of docking or interaction partners for transiently associated nuclear transport factors. May play a role in the association of MAD1 with the NPC.SUBUNIT Interacts with TMEM48/NDC1. Forms a complex with NUP93, NUP155, NUP205 and lamin B; the interaction with NUP93 is direct.SIMILARITY Belongs to the Nup35 family.UniProtQ8NFH51EQUAL326EQUALReactome Database ID Release 75157748Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157748ReactomeR-HSA-1577482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157748.21NUP205Nup205Reactome DB_ID: 157754UniProt:Q92621 NUP205NUP205C7orf14KIAA0225FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance (PubMed:9348540). May anchor NUP62 and other nucleoporins, but not NUP153 and TPR, to the NPC (PubMed:15229283).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:9348540, PubMed:15229283). Forms a complex with NUP35, NUP93, NUP155 and lamin B (PubMed:15703211, PubMed:26878725). Does not interact with TPR (PubMed:12802065).SIMILARITY Belongs to the NUP186/NUP192/NUP205 family.UniProtQ926212EQUAL2012EQUALReactome Database ID Release 75157754Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157754ReactomeR-HSA-1577541Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157754.11Reactome Database ID Release 759634183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9634183ReactomeR-HSA-96341831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9634183.132NUP188Nup188Reactome DB_ID: 157752UniProt:Q5SRE5 NUP188NUP188KIAA0169FUNCTION May function as a component of the nuclear pore complex (NPC).DISEASE Copy number variations of NUP188 gene may be a cause of heterotaxy, a congenital heart disease resulting from abnormalities in left-right (LR) body patterning.UniProtQ5SRE52EQUAL1749EQUALReactome Database ID Release 75157752Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157752ReactomeR-HSA-1577521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157752.116RAE1Rae1/Gle2Reactome DB_ID: 157718UniProt:P78406 RAE1RAE1MRNP41FUNCTION Plays a role in mitotic bipolar spindle formation (PubMed:17172455). Binds mRNA. May function in nucleocytoplasmic transport and in directly or indirectly attaching cytoplasmic mRNPs to the cytoskeleton.SUBUNIT Interacts with NUMA1 (via N-terminal end of the coiled-coil domain); this interaction promotes spindle formation in mitosis (PubMed:17172455). Interacts with NUP98 (PubMed:20498086). Interacts with MYCBP2 (PubMed:22357847).SIMILARITY Belongs to the WD repeat rae1 family.UniProtP784061EQUAL368EQUALReactome Database ID Release 75157718Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157718ReactomeR-HSA-1577181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157718.148Converted from EntitySet in ReactomePOM121Reactome DB_ID: 6805169POM121Reactome DB_ID: 157747UniProt:Q96HA1 POM121POM121KIAA0618NUP121POM121AFUNCTION Essential component of the nuclear pore complex (NPC). The repeat-containing domain may be involved in anchoring components of the pore complex to the pore membrane. When overexpressed in cells induces the formation of cytoplasmic annulate lamellae (AL).DOMAIN Contains F-X-F-G repeats.SIMILARITY Belongs to the POM121 family.UniProtQ96HA11EQUAL1249EQUALReactome Database ID Release 75157747Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157747ReactomeR-HSA-1577471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157747.1POM121CNuclear envelope pore membrane protein POM 121CP121C_HUMANReactome DB_ID: 6805165UniProt:A8CG34 POM121CPOM121CFUNCTION Essential component of the nuclear pore complex (NPC). The repeat-containing domain may be involved in anchoring components of the pore complex to the pore membrane. When overexpressed in cells induces the formation of cytoplasmic annulate lamellae (AL).DOMAIN Contains F-X-F-G repeats.SIMILARITY Belongs to the POM121 family.UniProtA8CG341EQUAL1229EQUALReactome Database ID Release 756805165Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805165ReactomeR-HSA-68051651Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805165.1Reactome Database ID Release 756805169Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805169ReactomeR-HSA-68051691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805169.116Converted from EntitySet in ReactomeNUP98Reactome DB_ID: 2990879NUP98-4Reactome DB_ID: 2990912UniProt:P52948-4 NUP98NUP98ADAR2FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change ASN-74-ASP is reduced (in vitro) (PubMed:23523133).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).SUBUNIT (Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).DOMAIN Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.PTM Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.DISEASE Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).DISEASE A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.DISEASE Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.DISEASE A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.DISEASE A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.DISEASE A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.SIMILARITY Belongs to the nucleoporin GLFG family.UniProt IsoformP52948-41EQUAL863EQUALReactome Database ID Release 752990912Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2990912ReactomeR-HSA-29909121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2990912.1NUP98-3Reactome DB_ID: 157723UniProt:P52948-3 NUP98NUP98ADAR2FUNCTION Plays a role in the nuclear pore complex (NPC) assembly and/or maintenance. NUP98 and NUP96 are involved in the bidirectional transport across the NPC. May anchor NUP153 and TPR to the NPC. In cooperation with DHX9, plays a role in transcription and alternative splicing activation of a subset of genes (PubMed:28221134). Involved in the localization of DHX9 in discrete intranuclear foci (GLFG-body) (PubMed:28221134).FUNCTION (Microbial infection) Binds HIV-1 capsid-nucleocapsid (HIV-1 CA-NC) complexes and may thereby promote the integration of the virus in the host nucleus (in vitro) (PubMed:23523133). Binding affinity to HIV-1 CA-NC complexes bearing the capsid change ASN-74-ASP is reduced (in vitro) (PubMed:23523133).SUBUNIT Part of the nuclear pore complex (NPC) (PubMed:15229283, PubMed:18287282). Interacts directly with NUP96 (PubMed:12191480). Part of the Nup160 subcomplex in the nuclear pore which is composed of NUP160, NUP133, NUP107 and NUP96; this complex plays a role in RNA export and in tethering NUP98 and NUP153 to the nucleus (PubMed:11684705). Interacts with RAE1 (PubMed:10209021, PubMed:20498086). Does not interact with TPR (PubMed:11684705). Interacts with NUP88 (PubMed:30543681). Interacts directly with NUP88 and NUP214, subunits of the cytoplasmic filaments of the NPC (By similarity). Interacts (via N-terminus) with DHX9 (via DRBM, OB-fold and RGG domains); this interaction occurs in a RNA-dependent manner and stimulates DHX9-mediated ATPase activity (PubMed:28221134).SUBUNIT (Microbial infection) Interacts with vesicular stomatitis virus protein M (PubMed:11106761).DOMAIN Contains G-L-F-G repeats. The FG repeat domains in Nup98 have a direct role in the transport.PTM Isoform 1 to isoform 4 are autoproteolytically cleaved to yield Nup98 and Nup96 or Nup98 only, respectively (PubMed:10087256, PubMed:20407419, PubMed:12191480, PubMed:18287282). Cleaved Nup98 is necessary for the targeting of Nup98 to the nuclear pore and the interaction with Nup96 (PubMed:20407419, PubMed:12191480).PTM Proteolytically degraded after poliovirus (PV) infection; degradation is partial and NCP- and TPR-binding domains withstand degradation.DISEASE Chromosomal aberrations involving NUP98 have been found in acute myeloid leukemia. Translocation t(7;11)(p15;p15) with HOXA9 (PubMed:8563753). Translocation t(11;17)(p15;p13) with PHF23 (PubMed:17287853).DISEASE A chromosomal aberration involving NUP98 has been found in M0 type acute myeloid leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in T-cell acute lymphocytic leukemia. Translocation t(4;11)(q23;p15) with RAP1GDS1.DISEASE A chromosomal aberration involving NUP98 has been found in M5 type acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE Chromosomal aberrations involving NUP98 have been found in childhood acute myeloid leukemia. Translocation t(5;11)(q35;p15.5) with NSD1. Translocation t(8;11)(p11.2;p15) with WHSC1L1.DISEASE Chromosomal aberrations involving NUP98 have been found in M7 type childhood acute myeloid leukemia. Translocation t(11;12)(p15;p13) with KDM5A.DISEASE A chromosomal aberration involving NUP98 is found in a form of therapy-related myelodysplastic syndrome. Translocation t(11;20)(p15;q11) with TOP1.DISEASE A chromosomal aberration involving NUP98 is found in a form of T-cell acute lymphoblastic leukemia (T-ALL). Translocation t(3;11)(q12.2;p15.4) with LNP1.DISEASE A chromosomal aberration involving NUP98 is associated with pediatric acute myeloid leukemia (AML) with intermediate characteristics between M2-M3 French-American-British (FAB) subtypes. Translocation t(9;11)(p22;p15) with PSIP1/LEDGF. The chimeric transcript is an in-frame fusion of NUP98 exon 8 to PSIP1/LEDGF exon 4.DISEASE A chromosomal aberration involving NUP98 has been identified in acute leukemias. Translocation t(6;11)(q24.1;p15.5) with CCDC28A. The chimeric transcript is an in-frame fusion of NUP98 exon 13 to CCDC28A exon 2. Ectopic expression of NUP98-CCDC28A in mouse promotes the proliferative capacity and self-renewal potential of hematopoietic progenitors and rapidly induced fatal myeloproliferative neoplasms and defects in the differentiation of the erythro-megakaryocytic lineage.SIMILARITY Belongs to the nucleoporin GLFG family.UniProt IsoformP52948-31EQUAL880EQUALReactome Database ID Release 75157723Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157723ReactomeR-HSA-1577231Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157723.1Reactome Database ID Release 752990879Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2990879ReactomeR-HSA-29908791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2990879.18NDC1Nucleoporin NDC1NDC1_HUMANReactome DB_ID: 6805183UniProt:Q9BTX1 NDC1NDC1TMEM48FUNCTION Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope. Required for NPC and nuclear envelope assembly, possibly by forming a link between the nuclear envelope membrane and soluble nucleoporins, thereby anchoring the NPC in the membrane.SUBUNIT Interacts with the NUP35/NUP53 (By similarity). Interacts with AAAS, anchoring it to the nuclear envelope.MISCELLANEOUS Depletion of NDC1 from HeLa cells interferes with the assembly of phenylalanine-glycine (FG) repeat Nups into nuclear pore complexes.SIMILARITY Belongs to the NDC1 family.UniProtQ9BTX11EQUAL674EQUALReactome Database ID Release 756805183Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=6805183ReactomeR-HSA-68051831Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-6805183.132AAASALADINReactome DB_ID: 157738UniProt:Q9NRG9 AAASAAASADRACALAGL003FUNCTION Plays a role in the normal development of the peripheral and central nervous system (PubMed:11062474, PubMed:11159947, PubMed:16022285). Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment (PubMed:26246606).SUBUNIT Interacts with NDC1, the interaction is required for nuclear pore localization (PubMed:19782045). Interacts with the inactive form aurora kinase AURKA (PubMed:26246606). Interacts with PGRMC2 (PubMed:27754849).TISSUE SPECIFICITY Widely expressed (PubMed:11159947, PubMed:16022285). Particularly abundant in cerebellum, corpus callosum, adrenal gland, pituitary gland, gastrointestinal structures and fetal lung (PubMed:11159947).UniProtQ9NRG91EQUAL546EQUALReactome Database ID Release 75157738Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157738ReactomeR-HSA-1577381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157738.18Nup62 ComplexReactome DB_ID: 157712Converted from EntitySet in ReactomeNUP58Reactome DB_ID: 9634224Nup58NUP58-1NUPL1-2NUPL1 isoform 2Reactome DB_ID: 157736UniProt:Q9BVL2-1 NUP58NUP58KIAA0410NUPL1FUNCTION Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.SUBUNIT Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58. Interacts with NUTF2. Interacts with SRP1-alpha and Importin p97 proteins when they are together, but not with SRP1-alpha protein alone (By similarity).DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.PTM O-glycosylated.MISCELLANEOUS In rat, the p62 complex contains two different isoforms of NUP58. Isoform p45 has however not been isolated in human so far.SIMILARITY Belongs to the NUP58 family.UniProt IsoformQ9BVL2-11EQUAL599EQUALReactome Database ID Release 75157736Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157736ReactomeR-HSA-1577362Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157736.2Nup45NUP58-2Reactome DB_ID: 157746UniProt:Q9BVL2-2 NUP58NUP58KIAA0410NUPL1FUNCTION Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.SUBUNIT Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58. Interacts with NUTF2. Interacts with SRP1-alpha and Importin p97 proteins when they are together, but not with SRP1-alpha protein alone (By similarity).DOMAIN Contains FG repeats. FG repeats are interaction sites for karyopherins (importins, exportins) and form probably an affinity gradient, guiding the transport proteins unidirectionally with their cargo through the NPC. FG repeat regions are highly flexible and lack ordered secondary structure. The overall conservation of FG repeats regarding exact sequence, spacing, and repeat unit length is limited.PTM O-glycosylated.MISCELLANEOUS In rat, the p62 complex contains two different isoforms of NUP58. Isoform p45 has however not been isolated in human so far.SIMILARITY Belongs to the NUP58 family.UniProt IsoformQ9BVL2-21EQUAL599EQUALReactome Database ID Release 75157746Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157746ReactomeR-HSA-1577462Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157746.2Reactome Database ID Release 759634224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9634224ReactomeR-HSA-96342241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9634224.11NUP54Nup54Reactome DB_ID: 157724UniProt:Q7Z3B4 NUP54NUP54FUNCTION Component of the nuclear pore complex, a complex required for the trafficking across the nuclear membrane.SUBUNIT Component of the p62 complex, a complex composed of NUP62, NUP54, and the isoform p58 and isoform p45 of NUP58. Interacts with NUTF2.DOMAIN Contains FG repeats.PTM O-glycosylated.SIMILARITY Belongs to the NUP54 family.UniProtQ7Z3B41EQUAL507EQUALReactome Database ID Release 75157724Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157724ReactomeR-HSA-1577241Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157724.11NUP62Nup62Reactome DB_ID: 157713UniProt:P37198 NUP62NUP62FUNCTION Essential component of the nuclear pore complex (PubMed:1915414). The N-terminal is probably involved in nucleocytoplasmic transport (PubMed:1915414). The C-terminal is involved in protein-protein interaction probably via coiled-coil formation, promotes its association with centrosomes and may function in anchorage of p62 to the pore complex (PubMed:1915414, PubMed:24107630). Plays a role in mitotic cell cycle progression by regulating centrosome segregation, centriole maturation and spindle orientation (PubMed:24107630). It might be involved in protein recruitment to the centrosome after nuclear breakdown (PubMed:24107630).SUBUNIT Component of the p62 complex, a complex at least composed of NUP62, NUP54, and NUP58 (By similarity). Interacts with NUP88 (PubMed:30543681). Interacts with NUTF2 (By similarity). Interacts with HIKESHI (PubMed:22541429). Interacts with OSBPL8 (PubMed:21698267). Interacts with CAPG (PubMed:18266911). Interacts with SAS6 and TUBG1 at the centrosome (PubMed:24107630). Interacts with MCM3AP isoform GANP (PubMed:23652018).SUBUNIT (Microbial infection) Interacts with Epstein-barr virus BGLF4; this interaction allows BGLF4 nuclear entry.DOMAIN Contains FG repeats.PTM O-glycosylated. Contains about 10 N-acetylglucosamine side chain sites predicted for the entire protein, among which only one in the C-terminal.PTM The inner channel of the NPC has a different redox environment from the cytoplasm and allows the formation of interchain disulfide bonds between some nucleoporins, the significant increase of these linkages upon oxidative stress reduces the permeability of the NPC.SIMILARITY Belongs to the nucleoporin NSP1/NUP62 family.UniProtP371981EQUAL522EQUALReactome Database ID Release 75157713Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157713ReactomeR-HSA-1577131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157713.11Reactome Database ID Release 75157712Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157712ReactomeR-HSA-1577122Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157712.232Reactome Database ID Release 75157689Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157689ReactomeR-HSA-1576894Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157689.4Reactome Database ID Release 753000418Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000418RANBP2E3 SUMO-protein ligase RanBP2 ecNumber6.3.2.-/ecNumberRBP2_HUMANNUP358Reactome DB_ID: 29937561EQUAL3224EQUALReactome Database ID Release 752993756Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993756ReactomeR-HSA-29937561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993756.1Reactome Database ID Release 755228508Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=5228508ReactomeR-HSA-52285082Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-5228508.215608651Pubmed2005Unique binding interactions among Ubc9, SUMO and RanBP2 reveal a mechanism for SUMO paralog selectionTatham, Michael HKim, SuhkmannJaffray, EllisSong, JingChen, YuanHay, Ronald TNat. Struct. Mol. Biol. 12:67-7416688858Pubmed2006In situ SUMOylation analysis reveals a modulatory role of RanBP2 in the nuclear rim and PML bodiesSaitoh, NorikoUchimura, YasuhiroTachibana, TaroSugahara, SatokoSaitoh, HisatoNakao, MitsuyoshiExp. Cell Res. 312:1418-30LEFT-TO-RIGHTConjugation of SUMO2 to PMLRANBP2 SUMOylates PML with SUMO2RANBP2 of the nuclear pore complex SUMOylates PML with SUMO2 at lysine-65, lysine-160, and lysine-490 (Kamitani et al. 1998, Tatham et al. 2005). RANBP2 contains both a binding site for SUMO1 and a binding site for UBE2I (Tatham et al. 2005). The binding site for UBE2I participates in SUMOylation of PML with SUMO2. SUMO2 colocalizes significantly with PML bodies (Vertegaal et al. 2004).Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-2366PML_HUMANSUMO2-K65,K160,K490-PMLSUMO2 N-glycyl-lys65,160,490 PMLProtein PMLReactome DB_ID: 300042365EQUAL160EQUAL490EQUAL1EQUAL882EQUALReactome Database ID Release 753000423Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000423ReactomeR-HSA-30004232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000423.2ACTIVATIONactiveUnit: #Protein107Reactome Database ID Release 753000411Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000411ReactomeR-HSA-30004112Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000411.215175327Pubmed2004A proteomic study of SUMO-2 target proteinsVertegaal, Alfred C OOgg, Stephen CJaffray, EllisRodriguez, Manuel SHay, Ronald TAndersen, JSMann, MatthiasLamond, Angus IJ. Biol. Chem. 279:33791-8LEFT-TO-RIGHTConjugation of SUMO3 to PMLSUMOylation of PML with SUMO3PML is observed to be SUMOylated with SUMO3 at lysine-65, lysine-160, and lysine-490 (Kamitani et al. 1998). SUMO3 is almost identical with SUMO2 therefore the same E3 ligase (RANBP2) that SUMOylate PML with SUMO2 may also be active with SUMO3, but this has not been proven. PML colocalizes with SUMO3 in nuclear bodies and disruption of SUMO3 expression reduces the number of nuclear bodies (Fu et al. 2005).Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-236PML_HUMANSUMO3-K65,K160,K490-PMLSUMO3 N-glycyl-lys65,160,490 PMLProtein PMLReactome DB_ID: 300038665EQUAL160EQUAL490EQUAL1EQUAL882EQUALReactome Database ID Release 753000386Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000386ReactomeR-HSA-30003862Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000386.26ACTIVATIONReactome Database ID Release 753246035Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3246035Reactome Database ID Release 753000433Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000433ReactomeR-HSA-30004331Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000433.116608850Pubmed2006Characterization of a family of nucleolar SUMO-specific proteases with preference for SUMO-2 or SUMO-3Gong, LiminYeh, Edward T HJ. Biol. Chem. 281:15869-7715940266Pubmed2005Stabilization of PML nuclear localization by conjugation and oligomerization of SUMO-3Fu, ChuanhaiAhmed, KashifDing, HushengDing, XiaLan, JianpingYang, ZhihongMiao, YongZhu, YuanyuanShi, YunyuZhu, JingdeHuang, HeYao, XOncogene 24:5401-13LEFT-TO-RIGHTSUMOylation of RAD52 with SUMO1RAD52 is SUMOylated at lysine-411, lysine-412, and lysine-414 with SUMO1. SUMOylation is important for localization of RAD52 to the nucleus.Authored: May, B, 2013-09-14Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-14RAD52DNA repair protein RAD52 homologReactome DB_ID: 62639UniProt:P43351 RAD52RAD52FUNCTION Involved in double-stranded break repair. Plays a central role in genetic recombination and DNA repair by promoting the annealing of complementary single-stranded DNA and by stimulation of the RAD51 recombinase.SUBUNIT The full-length protein forms heptameric rings. Interacts with ABL1. Interacts with RPA2; the interaction is direct and associates RAD52 with the RPA complex.PTM Phosphorylated upon DNA damage by ABL1, and probably by ATM or ATR.SIMILARITY Belongs to the RAD52 family.UniProtP433511EQUAL418EQUALReactome Database ID Release 7562639Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=62639ReactomeR-HSA-626391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-62639.133SUMO1:RAD52Reactome DB_ID: 4568880SUMO1_HUMANK414-RAD52-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456890097EQUAL2EQUAL97EQUALReactome Database ID Release 754568900Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568900ReactomeR-HSA-45689001Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568900.11SUMO1_HUMANK411-RAD52-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456885797EQUAL2EQUAL97EQUALReactome Database ID Release 754568857Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568857ReactomeR-HSA-45688571Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568857.11RAD52_HUMANSUMO1-K411,K412,K414-RAD52DNA repair protein RAD52 homologReactome DB_ID: 4568909411EQUAL412EQUAL414EQUAL1EQUAL418EQUALReactome Database ID Release 754568909Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568909ReactomeR-HSA-45689091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568909.11SUMO1_HUMANK412-RAD52-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456885097EQUAL2EQUAL97EQUALReactome Database ID Release 754568850Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568850ReactomeR-HSA-45688501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568850.11Reactome Database ID Release 754568880Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568880ReactomeR-HSA-45688801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568880.13ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754568863Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568863ReactomeR-HSA-45688632Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568863.220190268Pubmed2010The putative nuclear localization signal of the human RAD52 protein is a potential sumoylation siteSaito, KengoKagawa, WSuzuki, TakehiroSuzuki, HidekazuYokoyama, ShigeyukiSaitoh, HisatoTashiro, SatoshiDohmae, NaoshiKurumizaka, HJ. Biochem. 147:833-42LEFT-TO-RIGHTPIAS4 SUMOylates RNF168 with SUMO1PIAS4 SUMOylates RNF168 at an unknown lysine residue (Danielsen et al. 2012). Both RNF168 and HERC2 are SUMOylated at double-strand breaks in DNA. SUMOylation of RNF168 is required for its retention at double-strand breaks.Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-13RNF168E3 ubiquitin-protein ligase RNF168RN168_HUMANReactome DB_ID: 4551605UniProt:Q8IYW5 RNF168RNF168FUNCTION E3 ubiquitin-protein ligase required for accumulation of repair proteins to sites of DNA damage. Acts with UBE2N/UBC13 to amplify the RNF8-dependent histone ubiquitination. Recruited to sites of DNA damage at double-strand breaks (DSBs) by binding to ubiquitinated histone H2A and H2AX and amplifies the RNF8-dependent H2A ubiquitination, promoting the formation of 'Lys-63'-linked ubiquitin conjugates. This leads to concentrate ubiquitinated histones H2A and H2AX at DNA lesions to the threshold required for recruitment of TP53BP1 and BRCA1. Also recruited at DNA interstrand cross-links (ICLs) sites and promotes accumulation of 'Lys-63'-linked ubiquitination of histones H2A and H2AX, leading to recruitment of FAAP20/C1orf86 and Fanconi anemia (FA) complex, followed by interstrand cross-link repair. H2A ubiquitination also mediates the ATM-dependent transcriptional silencing at regions flanking DSBs in cis, a mechanism to avoid collision between transcription and repair intermediates. Also involved in class switch recombination in immune system, via its role in regulation of DSBs repair. Following DNA damage, promotes the ubiquitination and degradation of JMJD2A/KDM4A in collaboration with RNF8, leading to unmask H4K20me2 mark and promote the recruitment of TP53BP1 at DNA damage sites. Not able to initiate 'Lys-63'-linked ubiquitination in vitro; possibly due to partial occlusion of the UBE2N/UBC13-binding region. Catalyzes monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub, respectively).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer. Interacts with UBE2N/UBC13.DOMAIN The MIU motif (motif interacting with ubiquitin) mediates the interaction with both 'Lys-48'- and 'Lys-63'-linked ubiquitin chains (PubMed:19500350). The UMI motif mediates interaction with ubiquitin with a preference for 'Lys-63'-linked ubiquitin (PubMed:21041483). The specificity for different types of ubiquitin is mediated by juxtaposition of ubiquitin-binding motifs (MIU and UMI motifs) with LR motifs (LRMs) (PubMed:22742833).PTM Sumoylated with SUMO1 by PIAS4 in response to double-strand breaks (DSBs).PTM Ubiquitinated.SIMILARITY Belongs to the RNF168 family.CAUTION According to a well-established model, RNF168 cannot initiate H2A 'Lys-63'-linked ubiquitination and is recruited following RNF8-dependent histone ubiquitination to amplify H2A 'Lys-63'-linked ubiquitination (PubMed:19500350, PubMed:19203578 and PubMed:19203579). However, other data suggest that RNF168 is the priming ubiquitin ligase by mediating monoubiquitination of 'Lys-13' and 'Lys-15' of nucleosomal histone H2A (H2AK13Ub and H2AK15Ub respectively) (PubMed:22980979). These data suggest that RNF168 might be recruited to DSBs sites in a RNF8-dependent manner by binding to non-histone proteins ubiquitinated via 'Lys-63'-linked and initiates monoubiquitination of H2A, which is then amplified by RNF8 (PubMed:22980979). Additional evidence is however required to confirm these data.UniProtQ8IYW51EQUAL571EQUALReactome Database ID Release 754551605Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551605ReactomeR-HSA-45516051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551605.1SUMO1:RNF168Reactome DB_ID: 4551657SUMO1_HUMANRNF168-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 455163197EQUAL2EQUAL97EQUALReactome Database ID Release 754551631Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551631ReactomeR-HSA-45516311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551631.11RN168_HUMANSUMO1-RNF168E3 ubiquitin-protein ligase RNF168Reactome DB_ID: 45517501EQUAL571EQUALReactome Database ID Release 754551750Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551750ReactomeR-HSA-45517501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551750.11Reactome Database ID Release 754551657Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551657ReactomeR-HSA-45516571Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551657.1ACTIVATIONReactome Database ID Release 754551661Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551661ReactomeR-HSA-45516612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551661.2LEFT-TO-RIGHTSUMOylation of RPA1 (RPA70) with SUMO2,3RPA1 (RPA70) is SUMOylated at lysine-449 and lysine-577 with SUMO2,3 (Dou et al. 2010, Tammsalu et al. 2014). SUMOylation of RPA1 recruits RAD51 to sites of DNA damage to initiate repair through homologous recombination.Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-13RPA1DNA Replication factor A protein A1 (70kD)RPA70Replication protein A 70 kDa DNA-binding subunitRP-ARF-AReplication factor-A protein 1Single-stranded DNA-binding proteinReactome DB_ID: 68461UniProt:P27694 RPA1RPA1REPA1RPA70FUNCTION As part of the heterotrimeric replication protein A complex (RPA/RP-A), binds and stabilizes single-stranded DNA intermediates, that form during DNA replication or upon DNA stress. It prevents their reannealing and in parallel, recruits and activates different proteins and complexes involved in DNA metabolism (PubMed:27723720, PubMed:27723717). Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage (PubMed:9430682). In the cellular response to DNA damage, the RPA complex controls DNA repair and DNA damage checkpoint activation. Through recruitment of ATRIP activates the ATR kinase a master regulator of the DNA damage response (PubMed:24332808). It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage (PubMed:17765923). Also recruits to sites of DNA damage proteins like XPA and XPG that are involved in nucleotide excision repair and is required for this mechanism of DNA repair (PubMed:7697716). Plays also a role in base excision repair (BER) probably through interaction with UNG (PubMed:9765279). Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance (PubMed:17959650). As part of the alternative replication protein A complex, aRPA, binds single-stranded DNA and probably plays a role in DNA repair. Compared to the RPA2-containing, canonical RPA complex, may not support chromosomal DNA replication and cell cycle progression through S-phase. The aRPA may not promote efficient priming by DNA polymerase alpha but could support DNA synthesis by polymerase delta in presence of PCNA and replication factor C (RFC), the dual incision/excision reaction of nucleotide excision repair and RAD51-dependent strand exchange (PubMed:19996105).SUBUNIT Component of the canonical replication protein A complex (RPA), a heterotrimer composed of RPA1, RPA2 and RPA3 (PubMed:27723720, PubMed:27723717). Also component of the aRPA, the alternative replication protein A complex, a trimeric complex similar to the replication protein A complex/RPA but where RPA1 and RPA3 are associated with RPA4 instead of RPA2 (PubMed:7760808, PubMed:19116208). The DNA-binding activity may reside exclusively on the RPA1 subunit. Interacts with PRPF19; the PRP19-CDC5L complex is recruited to the sites of DNA repair where it ubiquitinates the replication protein A complex (RPA) (PubMed:24332808). Interacts with RIPK1 (PubMed:16135809). Interacts with the polymerase alpha subunit POLA1/p180; this interaction stabilizes the replicative complex and reduces the misincorporation rate of DNA polymerase alpha by acting as a fidelity clamp (PubMed:9214288). Interacts with RAD51 and SENP6 to regulate DNA repair (PubMed:20705237). Interacts with HELB; this interaction promotes HELB recruitment to chromatin following DNA damage (PubMed:22194613, PubMed:26774285). Interacts with PRIMPOL; leading to recruit PRIMPOL on chromatin and stimulate its DNA primase activity (PubMed:24126761, PubMed:25550423, PubMed:28534480). Interacts with XPA; the interaction is direct and associates XPA with the RPA complex (PubMed:7700386, PubMed:9699634, PubMed:10563794). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RPA1; this interaction associates HROB with the RPA complex (By similarity).PTM DNA damage-induced 'Lys-63'-linked polyubiquitination by PRPF19 mediates ATRIP recruitment to the RPA complex at sites of DNA damage and activation of ATR (PubMed:24332808). Ubiquitinated by RFWD3 at stalled replication forks in response to DNA damage: ubiquitination by RFWD3 does not lead to degradation by the proteasome and promotes removal of the RPA complex from stalled replication forks, promoting homologous recombination (PubMed:26474068).PTM Sumoylated on lysine residues Lys-449 and Lys-577, with Lys-449 being the major site. Sumoylation promotes recruitment of RAD51 to the DNA damage foci to initiate DNA repair through homologous recombination. Desumoylated by SENP6.SIMILARITY Belongs to the replication factor A protein 1 family.UniProtP276942EQUAL616EQUALReactome Database ID Release 7568461Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68461ReactomeR-HSA-684612Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68461.22RP-ASUMO2,3-K449,K577-RPA1DNA Replication factor A protein A1 (70kD)RPA70Replication protein A 70 kDa DNA-binding subunitRF-AReplication factor-A protein 1Single-stranded DNA-binding proteinReactome DB_ID: 4551644449EQUAL577EQUAL2EQUAL616EQUALReactome Database ID Release 754551644Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551644ReactomeR-HSA-45516442Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551644.24ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754551616Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551616ReactomeR-HSA-45516161Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551616.120705237Pubmed2010Regulation of DNA repair through deSUMOylation and SUMOylation of replication protein A complexDou, HongHuang, ChaoSingh, MelissaCarpenter, PBYeh, Edward T HMol. Cell 39:333-45LEFT-TO-RIGHTConjugation of SUMO1 to SP100RANBP2 SUMOylates SP100 with SUMO1RANBP2 SUMOylates SP100 with SUMO1 at lysine-297 (Pichler et al. 2002, Tatham et al. 2005). RANBP2 has a binding site for SUMO1 and a binding site for UBE2I (UBC9) which may recruit the SUMO1:UBE2I (SUMO1:UBC9) complex (Tatham et al. 2005). RANBP2 is located on the cytoplasmic filaments of the nuclear pore so that SUMOylation may occur during nuclear import of SP100 (Pichler et al. 2002)Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-23SP100Nuclear autoantigen Sp-100SP100_HUMANReactome DB_ID: 1031705UniProt:P23497 SP100SP100FUNCTION Together with PML, this tumor suppressor is a major constituent of the PML bodies, a subnuclear organelle involved in a large number of physiological processes including cell growth, differentiation and apoptosis. Functions as a transcriptional coactivator of ETS1 and ETS2 according to PubMed:11909962. Under certain conditions, it may also act as a corepressor of ETS1 preventing its binding to DNA according to PubMed:15247905. Through the regulation of ETS1 it may play a role in angiogenesis, controlling endothelial cell motility and invasion. Through interaction with the MRN complex it may be involved in the regulation of telomeres lengthening. May also regulate TP53-mediated transcription and through CASP8AP2, regulate FAS-mediated apoptosis. Also plays a role in infection by viruses, including human cytomegalovirus and Epstein-Barr virus, through mechanisms that may involve chromatin and/or transcriptional regulation.SUBUNIT Homodimer; isoforms are able to heterodimerize. Interacts with members of the HP1 family of nonhistone chromosomal protein, such as CBX5 and CBX3 via the PxVxL motif. Interacts with ETS1; the interaction is direct and modulates ETS1 transcriptional activity. Interacts with the MRN complex which is composed of two heterodimers RAD50/MRE11 associated with a single NBN; recruits the complex to PML-related bodies. Interacts with HIPK2; positively regulates TP53-dependent transcription. Interacts with CASP8AP2; may negatively regulate CASP8AP2 export from the nucleus to the cytoplasm. Interacts with SUMO1P1/SUMO5 (PubMed:27211601).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA-LP; this interaction is important for EBNA-LP coactivator activity.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123; may play a role in infection by the virus.TISSUE SPECIFICITY Widely expressed. Sp100-B is expressed only in spleen, tonsil, thymus, mature B-cell line and some T-cell line, but not in brain, liver, muscle or non-lymphoid cell lines.INDUCTION Up-regulated by interferon, retinoic acid, TNF-alpha/TNFA and lipopolysaccharide (at protein level). Up-regulated following heat-shock.DOMAIN The HSR domain is important for the nuclear body targeting as well as for the dimerization.DOMAIN Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.PTM Sumoylated. Sumoylation depends on a functional nuclear localization signal but is not necessary for nuclear import or nuclear body targeting.PTM Sumoylated. Sumoylated with SUMO1. Sumoylation depends on a functional nuclear localization signal but is not necessary for nuclear import or nuclear body targeting. Sumoylation may stabilize the interaction with CBX5.MISCELLANEOUS The major isoform Sp100-A, has a calculated molecular weight of 54 kDa, but exhibits aberrant electrophoretic mobilities, with an apparent molecular weight of 100 kDa.UniProtP234971EQUAL879EQUALReactome Database ID Release 751031705Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1031705ReactomeR-HSA-10317051Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1031705.1SUMO1:SP100Reactome DB_ID: 3730791SP100_HUMANSUMO1-K297-SP100SUMO1 N-glycyl-lys297 SP100Nuclear autoantigen Sp-100Reactome DB_ID: 3000382297EQUAL1EQUAL879EQUALReactome Database ID Release 753000382Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000382ReactomeR-HSA-30003821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000382.11SUMO1_HUMANSP100-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 373079497EQUAL2EQUAL97EQUALReactome Database ID Release 753730794Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730794ReactomeR-HSA-37307941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730794.11Reactome Database ID Release 753730791Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3730791ReactomeR-HSA-37307911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3730791.1ACTIVATIONactiveUnit: #Protein107Reactome Database ID Release 753000399Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000399ReactomeR-HSA-30003992Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000399.211792325Pubmed2002The nucleoporin RanBP2 has SUMO1 E3 ligase activityPichler, AndreaGast, AndreasSeeler, Jacob SDejean, AnneMelchior, FraukeCell 108:109-20LEFT-TO-RIGHTConjugation of SUMO2 to SP100RANBP2 SUMOylates SP100 with SUMO2RANBP2 of the nuclear pore complex SUMOylates SP100 with SUMO2 at lysine-297 (Tatham et al. 2005, Hendriks et al. 2014). RANBP2 binds UBE2I (UBC9) to facilitate the transfer of SUMO2 from SUMO2:UBE2I to SP100 (Tatham et al. 2005).Authored: May, B, 2013-01-23Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-01-2322SP100_HUMANSUMO2-K297-SP100SUMO2 N-glycyl-lys297 SP100Nuclear autoantigen Sp-100Reactome DB_ID: 3000454297EQUAL1EQUAL879EQUALReactome Database ID Release 753000454Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000454ReactomeR-HSA-30004543Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000454.3ACTIVATIONactiveUnit: #Protein107Reactome Database ID Release 753000348Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3000348ReactomeR-HSA-30003482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3000348.2LEFT-TO-RIGHTSUMOylation of TDG with SUMO1TDG is SUMOylated at lysine-330 with SUMO1 by UBE2I (Hardeland et al. 2002, Baba et al. 2005, Steinacher et al. 2005, Knipscheer et al. 2008, Smet-Nocca et al. 2011). Conjugation of SUMO1 to TDG induces dissociation of TDG from its product, an abasic site, and increases turnover of TDG with G:U substrate but abolishes activity with G:T substrate (Hardeland et al. 2002).Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-13TDGG/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)Reactome DB_ID: 65812UniProt:Q13569 TDGTDGFUNCTION DNA glycosylase that plays a key role in active DNA demethylation: specifically recognizes and binds 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in the context of CpG sites and mediates their excision through base-excision repair (BER) to install an unmethylated cytosine. Cannot remove 5-hydroxymethylcytosine (5hmC). According to an alternative model, involved in DNA demethylation by mediating DNA glycolase activity toward 5-hydroxymethyluracil (5hmU) produced by deamination of 5hmC. Also involved in DNA repair by acting as a thymine-DNA glycosylase that mediates correction of G/T mispairs to G/C pairs: in the DNA of higher eukaryotes, hydrolytic deamination of 5-methylcytosine to thymine leads to the formation of G/T mismatches. Its role in the repair of canonical base damage is however minor compared to its role in DNA demethylation. It is capable of hydrolyzing the carbon-nitrogen bond between the sugar-phosphate backbone of the DNA and a mispaired thymine. In addition to the G/T, it can remove thymine also from C/T and T/T mispairs in the order G/T >> C/T > T/T. It has no detectable activity on apyrimidinic sites and does not catalyze the removal of thymine from A/T pairs or from single-stranded DNA. It can also remove uracil and 5-bromouracil from mispairs with guanine.SUBUNIT Homodimer. Interacts with AICDA and GADD45A.PTM Sumoylation on Lys-330 by either SUMO1 or SUMO2 induces dissociation of the product DNA.SIMILARITY Belongs to the uracil-DNA glycosylase (UDG) superfamily. TDG/mug family.UniProtQ135691EQUAL410EQUALReactome Database ID Release 7565812Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=65812ReactomeR-HSA-658121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-65812.1SUMO1:TDGReactome DB_ID: 4551594SUMO1_HUMANTDG-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 455168297EQUAL2EQUAL97EQUALReactome Database ID Release 754551682Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551682ReactomeR-HSA-45516821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551682.11SUMO1-K330-TDGG/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)Reactome DB_ID: 4551718330EQUAL1EQUAL410EQUALReactome Database ID Release 754551718Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551718ReactomeR-HSA-45517181Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551718.11Reactome Database ID Release 754551594Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551594ReactomeR-HSA-45515941Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551594.1ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754551648Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551648ReactomeR-HSA-45516482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551648.211889051Pubmed2002Modification of the human thymine-DNA glycosylase by ubiquitin-like proteins facilitates enzymatic turnoverHardeland, UlrikeSteinacher, RolandJiricny, JosefSchär, PrimoEMBO J. 21:1456-6421284855Pubmed2011SUMO-1 regulates the conformational dynamics of thymine-DNA Glycosylase regulatory domain and competes with its DNA binding activitySmet-Nocca, CarolineWieruszeski, Jean-MichelLéger, HélèneEilebrecht, SebastianBenecke, ArndtBMC Biochem. 12:415823533Pubmed2005Functionality of human thymine DNA glycosylase requires SUMO-regulated changes in protein conformationSteinacher, RolandSchär, PrimoCurr. Biol. 15:616-2315959518Pubmed2005Crystal structure of thymine DNA glycosylase conjugated to SUMO-1Baba, DaichiMaita, NobuoJee, Jun-GooUchimura, YasuhiroSaitoh, HisatoSugasawa, KaoruHanaoka, FumioTochio, HidehitoHiroaki, HidekazuShirakawa, MasahiroNature 435:979-82LEFT-TO-RIGHTSUMOylation of TDG with SUMO2,3TDG is SUMOylated at lysine-330 with SUMO2,3 by UBE2I and perhaps another E3 ligase (Hardeland et al. 2002, Baba et al. 2006, Hendriks et al. 2014, Tammsalu et al. 2014). SUMOylation increases turnover of TDG with G:U substrate and abolishes activity with G:T substrate (Hardeland et al. 2002).Authored: May, B, 2013-09-13Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-132SUMO2,3-K330-TDGG/T mismatch-specific thymine DNA glycosylase (EC 3.2.2.-)Reactome DB_ID: 4551628330EQUAL1EQUAL410EQUALReactome Database ID Release 754551628Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551628ReactomeR-HSA-45516282Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551628.2ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754551738Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4551738ReactomeR-HSA-45517381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4551738.116626738Pubmed2006Crystal structure of SUMO-3-modified thymine-DNA glycosylaseBaba, DaichiMaita, NobuoJee, Jun-GooUchimura, YasuhiroSaitoh, HisatoSugasawa, KaoruHanaoka, FumioTochio, HidehitoHiroaki, HidekazuShirakawa, MasahiroJ. Mol. Biol. 359:137-47LEFT-TO-RIGHTCDKN2A (p14-ARF) SUMOylates WRN with SUMO1CDKN2A (p14-ARF) SUMOylates WRN at lysine-356, lysine-496, and lysine-898 with SUMO1 (Woods et al. 2004). SUMOylation of WRN causes it to be released from the nucleolus.Authored: May, B, 2013-09-14Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-14WRNWerner syndrome helicaseReactome DB_ID: 67387UniProt:Q14191 WRNWRNRECQ3RECQL2FUNCTION Multifunctional enzyme that has both magnesium and ATP-dependent DNA-helicase activity and 3'->5' exonuclease activity towards double-stranded DNA with a 5'-overhang. Has no nuclease activity towards single-stranded DNA or blunt-ended double-stranded DNA. Binds preferentially to DNA substrates containing alternate secondary structures, such as replication forks and Holliday junctions. May play an important role in the dissociation of joint DNA molecules that can arise as products of homologous recombination, at stalled replication forks or during DNA repair. Alleviates stalling of DNA polymerases at the site of DNA lesions. Important for genomic integrity. Plays a role in the formation of DNA replication focal centers; stably associates with foci elements generating binding sites for RP-A (By similarity). Plays a role in double-strand break repair after gamma-irradiation.SUBUNIT Monomer, and homooligomer. May exist as homodimer, homotrimer, homotetramer and/or homohexamer. Homotetramer, or homohexamer, when bound to DNA. Interacts via its N-terminal domain with WRNIP1 (By similarity). Interacts with EXO1, PCNA and SUPV3L1. Interacts with PML (isoform PML-4).PTM Phosphorylated by PRKDC.SIMILARITY Belongs to the helicase family. RecQ subfamily.UniProtQ141911EQUAL1432EQUALReactome Database ID Release 7567387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=67387ReactomeR-HSA-673871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-67387.133SUMO1:WRNReactome DB_ID: 4568903WRN_HUMANSUMO1-K356,K496,K898-WRNWerner syndrome ATP-dependent helicase ecNumber3.6.4.12/ecNumberReactome DB_ID: 4568904356EQUAL496EQUAL898EQUAL1EQUAL1432EQUALReactome Database ID Release 754568904Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568904ReactomeR-HSA-45689041Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568904.11SUMO1_HUMANK356-WRN-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456884597EQUAL2EQUAL97EQUALReactome Database ID Release 754568845Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568845ReactomeR-HSA-45688451Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568845.11SUMO1_HUMANK496-WRN-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456890697EQUAL2EQUAL97EQUALReactome Database ID Release 754568906Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568906ReactomeR-HSA-45689061Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568906.11SUMO1_HUMANK898-WRN-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456889397EQUAL2EQUAL97EQUALReactome Database ID Release 754568893Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568893ReactomeR-HSA-45688931Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568893.11Reactome Database ID Release 754568903Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568903ReactomeR-HSA-45689031Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568903.13ACTIVATIONp14ARFCyclin-dependent kinase inhibitor 2A, isoform 4p19ARFReactome DB_ID: 1629813UniProt:Q8N726 CDKN2ACDKN2ACDKN2MLMFUNCTION Capable of inducing cell cycle arrest in G1 and G2 phases. Acts as a tumor suppressor. Binds to MDM2 and blocks its nucleocytoplasmic shuttling by sequestering it in the nucleolus. This inhibits the oncogenic action of MDM2 by blocking MDM2-induced degradation of p53 and enhancing p53-dependent transactivation and apoptosis. Also induces G2 arrest and apoptosis in a p53-independent manner by preventing the activation of cyclin B1/CDC2 complexes. Binds to BCL6 and down-regulates BCL6-induced transcriptional repression. Binds to E2F1 and MYC and blocks their transcriptional activator activity but has no effect on MYC transcriptional repression. Binds to TOP1/TOPOI and stimulates its activity. This complex binds to rRNA gene promoters and may play a role in rRNA transcription and/or maturation. Interacts with NPM1/B23 and promotes its polyubiquitination and degradation, thus inhibiting rRNA processing. Interacts with COMMD1 and promotes its 'Lys63'-linked polyubiquitination. Interacts with UBE2I/UBC9 and enhances sumoylation of a number of its binding partners including MDM2 and E2F1. Binds to HUWE1 and represses its ubiquitin ligase activity. May play a role in controlling cell proliferation and apoptosis during mammary gland development. Isoform smARF may be involved in regulation of autophagy and caspase-independent cell death; the short-lived mitochondrial isoform is stabilized by C1QBP.SUBUNIT Does not interact with cyclins, CDK1, CDK2, CDK4, CDK5 or CDK6. Binds to BCL6, E2F1, HUWE1, MDM2, MYC, NPM1/B23, TOP1/TOPOI and UBE2I/UBC9. Interacts with TBRG1 and COMMD1. Interacts with CDKN2AIP and E4F1. Interacts with CDK5RAP3 and MDM2; form a ternary complex involved in regulation of p53/TP53 (PubMed:16173922). Isoform smARF interacts with C1QBP. Interacts with NOP53; the interaction is direct and promotes ARF nucleoplasmic relocalization and ubiquitin-mediated proteasomal degradation (PubMed:27323397).PTM Ubiquitinated in normal cells by TRIP12 via the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination at the N-terminus, regardless of the absence of lysine residues. Ubiquitination leads to its proteasomal degradation. In cancer cells, however, TRIP12 is located in a different cell compartment, preventing ubiquitination and degradation.CAUTION The proteins described here are encoded by the gene CDKN2A, but are completely unrelated in terms of sequence and function to cyclin-dependent kinase inhibitor 2A (AC P42771) which is encoded by the same gene.UniProtQ8N7261EQUAL132EQUALReactome Database ID Release 751629813Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1629813ReactomeR-HSA-16298132Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1629813.2Reactome Database ID Release 754568910Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568910Reactome Database ID Release 754568846Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568846ReactomeR-HSA-45688462Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568846.215355988Pubmed2004p14 Arf promotes small ubiquitin-like modifier conjugation of Werners helicaseWoods, Yvonne LXirodimas, Dimitris PPrescott, Alan RSparks, AlisonLane, David PSaville, Mark KJ. Biol. Chem. 279:50157-66LEFT-TO-RIGHTPIAS1,2-1 SUMOylates XRCC4 with SUMO1PIAS1,2-1 SUMOylate XRCC4 at lysine-210 with SUMO1 (Yurchenko et al. 2006). SUMOylation causes localization of XRCC4 to the nucleus. (An unSUMOylatable mutant of XRCC4 is localized to the cytosol.)Authored: May, B, 2013-09-14Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-14XRCC4DNA repair protein XRCC4 Reactome DB_ID: 75911UniProt:Q13426 XRCC4XRCC4FUNCTION Involved in DNA non-homologous end joining (NHEJ) required for double-strand break repair and V(D)J recombination. Binds to DNA and to DNA ligase IV (LIG4). The LIG4-XRCC4 complex is responsible for the NHEJ ligation step, and XRCC4 enhances the joining activity of LIG4. Binding of the LIG4-XRCC4 complex to DNA ends is dependent on the assembly of the DNA-dependent protein kinase complex DNA-PK to these DNA ends.SUBUNIT Homodimer and homotetramer in solution. The homodimer associates with LIG4. The LIG4-XRCC4 complex associates in a DNA-dependent manner with the DNA-PK complex composed of PRKDC, XRCC6/Ku70 and XRCC5/Ku86 to form the core non-homologous end joining (NHEJ) complex. Additional components of the NHEJ complex include NHEJ1/XLF and PAXX. Interacts directly with PRKDC but not with the XRCC6/Ku70 and XRCC5/Ku86 dimer. Interacts with APTX and APLF.TISSUE SPECIFICITY Widely expressed.PTM Phosphorylated by PRKDC. The phosphorylation seems not to be necessary for binding to DNA. Phosphorylation by CK2 promotes interaction with APTX.PTM Monoubiquitinated.PTM Sumoylation at Lys-210 is required for nuclear localization and recombination efficiency. Has no effect on ubiquitination.SIMILARITY Belongs to the XRCC4 family.UniProtQ134261EQUAL336EQUALReactome Database ID Release 7575911Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=75911ReactomeR-HSA-759111Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-75911.1SUMO1:XRCC4Reactome DB_ID: 4568891SUMO1-K210-XRCC4DNA repair protein XRCC4 Reactome DB_ID: 4568892210EQUAL1EQUAL336EQUALReactome Database ID Release 754568892Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568892ReactomeR-HSA-45688921Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568892.11SUMO1_HUMANXRCC4-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 456886997EQUAL2EQUAL97EQUALReactome Database ID Release 754568869Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568869ReactomeR-HSA-45688691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568869.11Reactome Database ID Release 754568891Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568891ReactomeR-HSA-45688911Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568891.1ACTIVATIONConverted from EntitySet in ReactomePIAS1,2-1Reactome DB_ID: 4090382PIAS2-1PIAS2 isoform 1E3 SUMO-protein ligase PIAS2 ecNumber6.3.2.-/ecNumberPIAS2_HUMANPIAS2xbetaReactome DB_ID: 2993785UniProt:O75928-1 PIAS2PIAS2PIASXFUNCTION Functions as an E3-type small ubiquitin-like modifier (SUMO) ligase, stabilizing the interaction between UBE2I and the substrate, and as a SUMO-tethering factor. Plays a crucial role as a transcriptional coregulator in various cellular pathways, including the STAT pathway, the p53 pathway and the steroid hormone signaling pathway. The effects of this transcriptional coregulation, transactivation or silencing may vary depending upon the biological context and the PIAS2 isoform studied. However, it seems to be mostly involved in gene silencing. Binds to sumoylated ELK1 and enhances its transcriptional activity by preventing recruitment of HDAC2 by ELK1, thus reversing SUMO-mediated repression of ELK1 transactivation activity. Isoform PIAS2-beta, but not isoform PIAS2-alpha, promotes MDM2 sumoylation. Isoform PIAS2-alpha promotes PARK7 sumoylation. Isoform PIAS2-beta promotes NCOA2 sumoylation more efficiently than isoform PIAS2-alpha. Isoform PIAS2-alpha sumoylates PML at'Lys-65' and 'Lys-160'.PATHWAY Protein modification; protein sumoylation.SUBUNIT Binds SUMO1 and UBE2I. Interacts with AXIN1, JUN, MDM2, PARK7, TP53 and TP73 isoform alpha, but not TP73 isoform beta. Interacts with STAT4 following IL12 and IFN-alpha stimulation of T-cells. Interacts also with GTF2I, GTF2IRD1, IKFZ1, DAB2 and MSX2, as well as with several steroid receptors, including ESR1, ESR2, NR3C1, PGR, AR, and with NCOA2 (By similarity). Sumoylation of a target protein seems to enhance the interaction. Binds to sumoylated ELK1. Binds DNA, such as CDKN1A promoter, in a sequence-specific manner. Interacts with PLAG1. Interacts with KLF8; the interaction results in SUMO ligation and repression of KLF8 transcriptional activity and of its cell cycle progression into G(1) phase. PIAS2-beta interacts with IFIH1/MDA5. Isoform PIAS2-alpha interacts with PML (isoform PML-12). Interacts with PRDM1/Blimp-1 (PubMed:28842558).TISSUE SPECIFICITY Mainly expressed in testis. Isoform 3 is expressed predominantly in adult testis, weakly in pancreas, embryonic testis and sperm, and at very low levels in other organs.DEVELOPMENTAL STAGE Isoform 3 expression in adult testis is 14.2-fold stronger than in embryonic testis.INDUCTION Up-regulated transiently during myeloid differentiation in various cells lines, such as HL-60, U-937, K-562, induced by either phorbol ester (TPA) or retinoic acid.DOMAIN The LXXLL motif is a transcriptional coregulator signature.PTM Sumoylated.SIMILARITY Belongs to the PIAS family.UniProt IsoformO75928-11EQUAL621EQUALReactome Database ID Release 752993785Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2993785ReactomeR-HSA-29937851Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2993785.1Reactome Database ID Release 754090382Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4090382ReactomeR-HSA-40903821Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4090382.1Reactome Database ID Release 754090313Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4090313Reactome Database ID Release 754568848Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4568848ReactomeR-HSA-45688482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4568848.216478998Pubmed2006SUMO modification of human XRCC4 regulates its localization and function in DNA double-strand break repairYurchenko, VyacheslavXue, ZhuSadofsky, Moshe JMol. Cell. Biol. 26:1786-94LEFT-TO-RIGHTSUMOylation of XPC with SUMO1XPC is SUMOylated at lysine-655 with SUMO1 (Wang et al. 2005, 2007). SUMOylation occurs after UV irradiation and may target XPC for destruction (Wang et al. 2007).Authored: May, B, 2013-09-19Reviewed: Ferrari, Stefano, 2015-02-21Edited: May, B, 2013-09-19XPCXPC proteinDNA-repair protein complementing XP-C cells (Xeroderma pigmentosum group C complementing protein) (P125)xeroderma pigmentosum, complementation group CDNA-repair protein complementing XP-C cellsXeroderma pigmentosum group C complementing proteinp125Reactome DB_ID: 67441UniProt:Q01831 XPCXPCXPCCFUNCTION Involved in global genome nucleotide excision repair (GG-NER) by acting as damage sensing and DNA-binding factor component of the XPC complex (PubMed:10734143, PubMed:19609301, PubMed:20649465, PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). Has only a low DNA repair activity by itself which is stimulated by RAD23B and RAD23A. Has a preference to bind DNA containing a short single-stranded segment but not to damaged oligonucleotides (PubMed:10734143, PubMed:19609301, PubMed:20649465). This feature is proposed to be related to a dynamic sensor function: XPC can rapidly screen duplex DNA for non-hydrogen-bonded bases by forming a transient nucleoprotein intermediate complex which matures into a stable recognition complex through an intrinsic single-stranded DNA-binding activity (PubMed:10734143, PubMed:19609301, PubMed:20649465). The XPC complex is proposed to represent the first factor bound at the sites of DNA damage and together with other core recognition factors, XPA, RPA and the TFIIH complex, is part of the pre-incision (or initial recognition) complex (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). The XPC complex recognizes a wide spectrum of damaged DNA characterized by distortions of the DNA helix such as single-stranded loops, mismatched bubbles or single-stranded overhangs (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). The orientation of XPC complex binding appears to be crucial for inducing a productive NER (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). XPC complex is proposed to recognize and to interact with unpaired bases on the undamaged DNA strand which is followed by recruitment of the TFIIH complex and subsequent scanning for lesions in the opposite strand in a 5'-to-3' direction by the NER machinery (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). Cyclobutane pyrimidine dimers (CPDs) which are formed upon UV-induced DNA damage esacpe detection by the XPC complex due to a low degree of structural perurbation. Instead they are detected by the UV-DDB complex which in turn recruits and cooperates with the XPC complex in the respective DNA repair (PubMed:9734359, PubMed:10873465, PubMed:12509299, PubMed:12547395, PubMed:19941824, PubMed:20028083, PubMed:20798892). In vitro, the XPC:RAD23B dimer is sufficient to initiate NER; it preferentially binds to cisplatin and UV-damaged double-stranded DNA and also binds to a variety of chemically and structurally diverse DNA adducts (PubMed:20028083). XPC:RAD23B contacts DNA both 5' and 3' of a cisplatin lesion with a preference for the 5' side. XPC:RAD23B induces a bend in DNA upon binding. XPC:RAD23B stimulates the activity of DNA glycosylases TDG and SMUG1 (PubMed:20028083).FUNCTION In absence of DNA repair, the XPC complex also acts as a transcription coactivator: XPC interacts with the DNA-binding transcription factor E2F1 at a subset of promoters to recruit KAT2A and histone acetyltransferase complexes (HAT) (PubMed:29973595, PubMed:31527837). KAT2A recruitment specifically promotes acetylation of histone variant H2A.Z.1/H2A.Z, but not H2A.Z.2/H2A.V, thereby promoting expression of target genes (PubMed:31527837).SUBUNIT Component of the XPC complex composed of XPC, RAD23B and CETN2 (PubMed:11279143, PubMed:12509233, PubMed:15964821, PubMed:17897675, PubMed:16627479, PubMed:16533048). Interacts with RAD23A; the interaction is suggesting the existence of a functional equivalent variant XPC complex (PubMed:9372924). Interacts with TDG; the interaction is demonstrated using the XPC:RAD23B dimer (PubMed:12505994, PubMed:20798892). Interacts with SMUG1; the interaction is demonstrated using the XPC:RAD23B dimer (PubMed:20798892). Interacts with DDB2 (PubMed:15882621). Interacts with CCNH, GTF2H1 and ERCC3 (PubMed:10734143, PubMed:12509233). Interacts with E2F1 and KAT2A; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837).PTM Ubiquitinated upon UV irradiation; the ubiquitination requires the UV-DDB complex, appears to be reversible and does not serve as a signal for degradation (PubMed:15882621, PubMed:23751493). Ubiquitinated by RNF11 via 'Lys-63'-linked ubiquitination (PubMed:23751493). Ubiquitination by RNF111 is polysumoylation-dependent and promotes nucleotide excision repair (PubMed:23751493).PTM Sumoylated; sumoylation promotes ubiquitination by RNF111.SIMILARITY Belongs to the XPC family.UniProtQ018312EQUAL940EQUALReactome Database ID Release 7567441Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=67441ReactomeR-HSA-674411Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-67441.1SUMO1:XPCReactome DB_ID: 4570501XPC_HUMANSUMO1-K655-XPCDNA repair protein complementing XP-C cellsReactome DB_ID: 4570458655EQUAL2EQUAL940EQUALReactome Database ID Release 754570458Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570458ReactomeR-HSA-45704581Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570458.11SUMO1_HUMANXPC-G97-SUMO1Small ubiquitin-related modifier 1Reactome DB_ID: 457045297EQUAL2EQUAL97EQUALReactome Database ID Release 754570452Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570452ReactomeR-HSA-45704521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570452.11Reactome Database ID Release 754570501Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570501ReactomeR-HSA-45705011Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570501.1ACTIVATIONactiveUnit: #Protein7Reactome Database ID Release 754570528Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=4570528ReactomeR-HSA-45705282Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-4570528.217693435Pubmed2007Ubiquitylation-independent degradation of Xeroderma pigmentosum group C protein is required for efficient nucleotide excision repairWang, Qi-EnPraetorius-Ibba, MetteZhu, QianzhengEl-Mahdy, Mohamed AWani, GulzarZhao, QunQin, SongPatnaik, SrinivasWani, Altaf ANucleic Acids Res. 35:5338-5016030353Pubmed2005DNA repair factor XPC is modified by SUMO-1 and ubiquitin following UV irradiationWang, Qi-EnZhu, QianzhengWani, GulzarEl-Mahdy, Mohamed ALi, JinyouWani, Altaf ANucleic Acids Res. 33:4023-34Reactome Database ID Release 753108214Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3108214ReactomeR-HSA-31082142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3108214.222357966Pubmed2012Ubiquitin and SUMO in DNA repair at a glanceUlrich, Helle DJ. Cell. Sci. 125:249-5421664912Pubmed2011The ubiquitin- and SUMO-dependent signaling response to DNA double-strand breaksBekker-Jensen, SimonMailand, NielsFEBS Lett. 585:2914-923416108Pubmed2013Regulation of DNA damage responses by ubiquitin and SUMOJackson, Stephen PDurocher, DanielMol. Cell 49:795-80723122649Pubmed2012Protein group modification and synergy in the SUMO pathway as exemplified in DNA repairPsakhye, IvanJentsch, StefanCell 151:807-2022018829Pubmed2012SUMO playing tag with ubiquitinPraefcke, Gerrit J KHofmann, KayDohmen, R JürgenTrends Biochem. Sci. 37:23-3121486569Pubmed2011SUMOylation and de-SUMOylation in response to DNA damageDou, HongHuang, ChaoVan Nguyen, ThangLu, Long-ShengYeh, Edward T HFEBS Lett. 585:2891-621896653Pubmed2011Shared and unique properties of ubiquitin and SUMO interaction networks in DNA repairvan Wijk, Sjoerd J LMüller, StefanDikic, IvanGenes Dev. 25:1763-924926426Pubmed2012Sumoylation and the DNA damage responseCremona, Catherine ASarangi, PrabhaZhao, XiaolanBiomolecules 2:376-8823781231Pubmed2013It takes two to tango: Ubiquitin and SUMO in the DNA damage responseBologna, SerenaFerrari, StefanoFront Genet 4:10623746258Pubmed2013Sumoylation: a regulatory protein modification in health and diseaseFlotho, AnnetteMelchior, FraukeAnnu. Rev. Biochem. 82:357-85