BioPAX pathway converted from "USP43 deISGylates ISG:K164,ISG:K168-PCNA" in the Reactome database. LEFT-TO-RIGHT USP43 deISGylates ISG:K164,ISG:K168-PCNA USP43 acts as an ISG15 protease to cleave ISG15 from lysines K164 and K168 of PCNA, thus deISGylating PCNA (Park et al. 2014). Authored: Orlic-Milacic, Marija, 2014-12-11 Reviewed: Borowiec, James, 2015-01-07 Edited: Orlic-Milacic, Marija, 2014-12-11 H2O water Reactome DB_ID: 113518 nucleoplasm GENE ONTOLOGY GO:0005654 water [ChEBI:15377] water ChEBI CHEBI:15377 Reactome Database ID Release 78 113518 Database 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=113518 Reactome R-ALL-113518 3 Reactome 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-ALL-113518.3 Reactome http://www.reactome.org COMPOUND C00001 additional information MI MI:0361 2 USP43:ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template Reactome DB_ID: 5653781 ISG:K164,ISG:K168-PCNA:RPA:RFC:TLS-DNA Template Reactome DB_ID: 5653772 Converted from EntitySet in Reactome TLS-DNA Template Reactome DB_ID: 5653662 (AP:Cyt-mispaireddNMPs)-DNA Template Reactome DB_ID: 5652148 Reactome Database ID Release 78 5652148 Database 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=5652148 Reactome R-HSA-5652148 2 Reactome 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-5652148.2 ChEBI 16991 (TT-CPD:AA-polydNMP)-DNA Template Reactome DB_ID: 5654979 Reactome Database ID Release 78 5654979 Database 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=5654979 Reactome R-HSA-5654979 2 Reactome 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-5654979.2 ChEBI 16991 Converted from EntitySet in Reactome (Tg:A-mispaireddNMPs)-DNA Template,(OGUA:A-mispaireddNMPs)-DNA Template,(BPDE-G:C-mispaireddNMPs)-DNA Template Reactome DB_ID: 5655964 (BPDE-G:C-mispaireddNMPs)-DNA Template DNA template with benzo(a)pyrene diol epoxide guanine adduct paired with cytosine (3'dCMP elongated with mispaired dNMPs) Reactome DB_ID: 5655958 Reactome Database ID Release 78 5655958 Database 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=5655958 Reactome R-HSA-5655958 2 Reactome 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-5655958.2 ChEBI 16991 (OGUA:A-mispaireddNMPs)-DNA Template DNA template containing 8-oxoguanine mispaired with adenine (3'dAMP elongated with mispaired dNMPs) Reactome DB_ID: 5655967 Reactome Database ID Release 78 5655967 Database 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=5655967 Reactome R-HSA-5655967 2 Reactome 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-5655967.2 ChEBI 16991 (Tg:A-mispaireddNMPs)-DNA Template DNA template containing thymine glycol paired with adenine (3'dAMP elongated with mispaired dNMPs) Reactome DB_ID: 5655966 Reactome Database ID Release 78 5655966 Database 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=5655966 Reactome R-HSA-5655966 2 Reactome 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-5655966.2 ChEBI 16991 Reactome Database ID Release 78 5655964 Database 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=5655964 Reactome R-HSA-5655964 1 Reactome 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-5655964.1 Converted from EntitySet in Reactome (EtAD:T-mispaireddNMPs)-DNA Template,(Gamma-HOPdG:C-mispaireddNMPs)-DNA Template Reactome DB_ID: 5656155 (EtAD:T-mispaireddNMPs)-DNA Template Reactome DB_ID: 5656160 Reactome Database ID Release 78 5656160 Database 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=5656160 Reactome R-HSA-5656160 2 Reactome 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-5656160.2 ChEBI 16991 (Gamma-HOPdG:C-mispaireddNMPs)-DNA Template Reactome DB_ID: 5656157 Reactome Database ID Release 78 5656157 Database 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=5656157 Reactome R-HSA-5656157 2 Reactome 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-5656157.2 ChEBI 16991 Reactome Database ID Release 78 5656155 Database 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=5656155 Reactome R-HSA-5656155 1 Reactome 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-5656155.1 Reactome Database ID Release 78 5653662 Database 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=5653662 Reactome R-HSA-5653662 1 Reactome 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-5653662.1 1 RFC Heteropentamer Reactome DB_ID: 68436 RFC2 RFC40 Activator 1 40 kDa subunit Replication factor C 40 kDa subunit A1 40 kDa subunit RF-C 40 kDa subunit Reactome DB_ID: 68433 UniProt:P35250 RFC2 RFC2 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit binds ATP (By similarity).SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA. RFC2 also interacts with PRKAR1A; the complex may be involved in cell survival (PubMed:15655353). Interacts with DDX11 (PubMed:18499658).DISEASE RFC2 is located in the Williams-Beuren syndrome (WBS) critical region. WBS results from a hemizygous deletion of several genes on chromosome 7q11.23, thought to arise as a consequence of unequal crossing over between highly homologous low-copy repeat sequences flanking the deleted region (PubMed:11003705).SIMILARITY Belongs to the activator 1 small subunits family. Homo sapiens NCBI Taxonomy 9606 UniProt P35250 1 EQUAL 354 EQUAL Reactome Database ID Release 78 68433 Database 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=68433 Reactome R-HSA-68433 2 Reactome 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-68433.2 1 RFC4 RFC37 Activator 1 37 kDa subunit Replication factor C 37 kDa subunit A1 37 kDa subunit RF-C 37 kDa subunit Reactome DB_ID: 68429 UniProt:P35249 RFC4 RFC4 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1. This subunit may be involved in the elongation of the multiprimed DNA template.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.MISCELLANEOUS Despite of the presence of a putative ATP-binding motif, this protein does not bind ATP.SIMILARITY Belongs to the activator 1 small subunits family. UniProt P35249 1 EQUAL 363 EQUAL Reactome Database ID Release 78 68429 Database 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=68429 Reactome R-HSA-68429 2 Reactome 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-68429.2 1 RFC3 RFC38 Activator 1 38 kDa subunit Replication factor C 38 kDa subunit A1 38 kDa subunit RF-C 38 kDa subunit Replication factor C subunit 3 Reactome DB_ID: 68431 UniProt:P40938 RFC3 RFC3 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.SIMILARITY Belongs to the activator 1 small subunits family. UniProt P40938 1 EQUAL 356 EQUAL Reactome Database ID Release 78 68431 Database 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=68431 Reactome R-HSA-68431 2 Reactome 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-68431.2 1 RFC1 RFC140 Activator 1 140 kDa subunit Replication factor C large subunit A1 140 kDa subunit RF-C 140 kDa subunit Activator 1 large subunit DNA-binding protein PO-GA Reactome DB_ID: 68435 UniProt:P35251 RFC1 RFC1 RFC140 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins PCNA and activator 1. This subunit binds to the primer-template junction. Binds the PO-B transcription element as well as other GA rich DNA sequences. Could play a role in DNA transcription regulation as well as DNA replication and/or repair. Can bind single- or double-stranded DNA.FUNCTION Interacts with C-terminus of PCNA. 5' phosphate residue is required for binding of the N-terminal DNA-binding domain to duplex DNA, suggesting a role in recognition of non-primer template DNA structures during replication and/or repair.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.TISSUE SPECIFICITY Wide tissue distribution. Undetectable in placental tissue.SIMILARITY Belongs to the activator 1 large subunit family. UniProt P35251 1 EQUAL 1148 EQUAL Reactome Database ID Release 78 68435 Database 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=68435 Reactome R-HSA-68435 2 Reactome 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-68435.2 1 RFC5 RFC36 Activator 1 36 kDa subunit (Replication factor C 36 kDa subunit) (A1 36 kDa subunit) (RF-C 36 kDa subunit) (RFC36) Activator 1 36 kDa subunit Replication factor C 36 kDa subunit A1 36 kDa subunit RF-C 36 kDa subunit Replication factor C subunit 5 Reactome DB_ID: 68427 UniProt:P40937 RFC5 RFC5 FUNCTION The elongation of primed DNA templates by DNA polymerase delta and epsilon requires the action of the accessory proteins proliferating cell nuclear antigen (PCNA) and activator 1.SUBUNIT Heterotetramer of subunits RFC2, RFC3, RFC4 and RFC5 that can form a complex either with RFC1 or with RAD17. The former interacts with PCNA in the presence of ATP, while the latter has ATPase activity but is not stimulated by PCNA.SIMILARITY Belongs to the activator 1 small subunits family. UniProt P40937 1 EQUAL 340 EQUAL Reactome Database ID Release 78 68427 Database 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=68427 Reactome R-HSA-68427 2 Reactome 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-68427.2 1 Reactome Database ID Release 78 68436 Database 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=68436 Reactome R-HSA-68436 1 Reactome 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-68436.1 ComplexPortal CPX-415 1 ISG:K164,ISG:K168-PCNA homotrimer Reactome DB_ID: 5653771 PCNA Proliferating cell nuclear antigen Cyclin Reactome DB_ID: 68439 UniProt:P12004 PCNA PCNA FUNCTION Auxiliary protein of DNA polymerase delta and is involved in the control of eukaryotic DNA replication by increasing the polymerase's processibility during elongation of the leading strand. Induces a robust stimulatory effect on the 3'-5' exonuclease and 3'-phosphodiesterase, but not apurinic-apyrimidinic (AP) endonuclease, APEX2 activities. Has to be loaded onto DNA in order to be able to stimulate APEX2. Plays a key role in DNA damage response (DDR) by being conveniently positioned at the replication fork to coordinate DNA replication with DNA repair and DNA damage tolerance pathways (PubMed:24939902). Acts as a loading platform to recruit DDR proteins that allow completion of DNA replication after DNA damage and promote postreplication repair: Monoubiquitinated PCNA leads to recruitment of translesion (TLS) polymerases, while 'Lys-63'-linked polyubiquitination of PCNA is involved in error-free pathway and employs recombination mechanisms to synthesize across the lesion (PubMed:24695737).SUBUNIT Homotrimer (PubMed:24939902). Interacts with p300/EP300; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with CREBBP (via transactivation domain and C-terminus); the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Directly interacts with POLD1, POLD3 and POLD4 subunits of the DNA polymerase delta complex, POLD3 being the major interacting partner; the interaction with POLD3 is inhibited by CDKN1A/p21(CIP1) (PubMed:11595739, PubMed:16510448, PubMed:22148433, PubMed:24939902). Forms a complex with activator 1 heteropentamer in the presence of ATP. Interacts with EXO1, POLH, POLK, DNMT1, ERCC5, FEN1, CDC6 and POLDIP2 (PubMed:9305916, PubMed:9302295, PubMed:9566895, PubMed:11784855, PubMed:12522211, PubMed:15225546, PubMed:15149598, PubMed:24911150, PubMed:15616578). Interacts with APEX2; this interaction is triggered by reactive oxygen species and increased by misincorporation of uracil in nuclear DNA (PubMed:11376153, PubMed:19443450). Forms a ternary complex with DNTTIP2 and core histone (PubMed:12786946). Interacts with KCTD10 and PPP1R15A (By similarity). Directly interacts with BAZ1B (PubMed:15543136). Interacts with HLTF and SHPRH (PubMed:17130289, PubMed:18316726, PubMed:18719106). Interacts with NUDT15; this interaction is disrupted in response to UV irradiation and acetylation (PubMed:19419956). Interacts with CDKN1A/p21(CIP1) and CDT1; interacts via their PIP-box which also recruits the DCX(DTL) complex. The interaction with CDKN1A inhibits POLD3 binding (PubMed:11595739, PubMed:16949367, PubMed:18794347, PubMed:18703516). Interacts with DDX11 (PubMed:18499658). Interacts with EGFR; positively regulates PCNA (PubMed:17115032). Interacts with PARPBP (PubMed:22153967). Interacts (when ubiquitinated) with SPRTN; leading to enhance RAD18-mediated PCNA ubiquitination (PubMed:22681887, PubMed:27084448). Interacts (when polyubiquitinated) with ZRANB3 (PubMed:22704558, PubMed:22705370, PubMed:22759634). Interacts with SMARCAD1 (PubMed:21549307). Interacts with CDKN1C (PubMed:22634751). Interacts with PCLAF (via PIP-box) (PubMed:21628590, PubMed:23000965). Interacts with RTEL1 (via PIP-box); the interaction is direct and essential for the suppression of telomere fragility (PubMed:24115439). Interacts with FAM111A (via PIP-box); the interaction is direct and required for PCNA loading on chromatin binding (PubMed:24561620). Interacts with LIG1 (PubMed:24911150). Interacts with SETMAR (PubMed:20457750). Interacts with ANKRD17 (PubMed:23711367). Interacts with FBXO18/FBH1 (via PIP-box); the interaction recruits the DCX(DTL) complex and promotes ubiquitination and degradation of FBXO18/FBH1 (PubMed:23677613). Interacts with POLN (PubMed:19995904). Interacts with SDE2 (via PIP-box); the interaction is direct and prevents ultraviolet light induced monoubiquitination (PubMed:27906959). Component of the replisome complex composed of at least DONSON, MCM2, MCM7, PCNA and TICRR; interaction at least with PCNA occurs during DNA replication (PubMed:28191891). Interacts with MAPK15; the interaction is chromatin binding dependent and prevents MDM2-mediated PCNA destruction by inhibiting the association of PCNA with MDM2 (PubMed:20733054). Interacts with PARP10 (via PIP-box) (PubMed:24695737). Interacts with DDI2 (PubMed:29290612). Interacts with HMCES (via PIP-box) (PubMed:30554877). Interacts with TRAIP (via PIP-box) (PubMed:27462463, PubMed:26711499).SUBUNIT (Microbial infection) Interacts with herpes virus 8 protein LANA1.PTM Phosphorylated. Phosphorylation at Tyr-211 by EGFR stabilizes chromatin-associated PCNA.PTM Acetylated by CREBBP and p300/EP300; preferentially acetylated by CREBBP on Lys-80, Lys-13 and Lys-14 and on Lys-77 by p300/EP300 upon loading on chromatin in response to UV irradiation (PubMed:24939902, PubMed:19419956). Lysine acetylation disrupts association with chromatin, hence promoting PCNA ubiquitination and proteasomal degradation in response to UV damage in a CREBBP- and EP300-dependent manner (PubMed:24939902). Acetylation disrupts interaction with NUDT15 and promotes degradation (PubMed:19419956).PTM Ubiquitinated (PubMed:24939902, PubMed:20227374). Following DNA damage, can be either monoubiquitinated to stimulate direct bypass of DNA lesions by specialized DNA polymerases or polyubiquitinated to promote recombination-dependent DNA synthesis across DNA lesions by template switching mechanisms. Following induction of replication stress, monoubiquitinated by the UBE2B-RAD18 complex on Lys-164, leading to recruit translesion (TLS) polymerases, which are able to synthesize across DNA lesions in a potentially error-prone manner. An error-free pathway also exists and requires non-canonical polyubiquitination on Lys-164 through 'Lys-63' linkage of ubiquitin moieties by the E2 complex UBE2N-UBE2V2 and the E3 ligases, HLTF, RNF8 and SHPRH. This error-free pathway, also known as template switching, employs recombination mechanisms to synthesize across the lesion, using as a template the undamaged, newly synthesized strand of the sister chromatid. Monoubiquitination at Lys-164 also takes place in undamaged proliferating cells, and is mediated by the DCX(DTL) complex, leading to enhance PCNA-dependent translesion DNA synthesis. Sumoylated during S phase.PTM Methylated on glutamate residues by ARMT1/C6orf211.MISCELLANEOUS Antibodies against PCNA are present in sera from patients with systemic lupus erythematosus.SIMILARITY Belongs to the PCNA family. UniProt P12004 1 EQUAL 261 EQUAL Reactome Database ID Release 78 68439 Database 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=68439 Reactome R-HSA-68439 2 Reactome 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-68439.2 2 ISG:K164,ISG:K168-PCNA Reactome DB_ID: 5653767 ISG-K164,ISG-K168-PCNA Reactome DB_ID: 5653768 164 EQUAL N6-glycyl-L-lysine MOD MOD:00134 168 EQUAL 1 EQUAL 261 EQUAL Reactome Database ID Release 78 5653768 Database 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=5653768 Reactome R-HSA-5653768 1 Reactome 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-5653768.1 1 K164-PCNA-G157-ISG15 Reactome DB_ID: 5653745 UniProt:P05161 ISG15 ISG15 G1P2 UCRP FUNCTION Ubiquitin-like protein which plays a key role in the innate immune response to viral infection either via its conjugation to a target protein (ISGylation) or via its action as a free or unconjugated protein. ISGylation involves a cascade of enzymatic reactions involving E1, E2, and E3 enzymes which catalyze the conjugation of ISG15 to a lysine residue in the target protein. Its target proteins include IFIT1, MX1/MxA, PPM1B, UBE2L6, UBA7, CHMP5, CHMP2A, CHMP4B and CHMP6. Can also isgylate: EIF2AK2/PKR which results in its activation, DDX58/RIG-I which inhibits its function in antiviral signaling response, EIF4E2 which enhances its cap structure-binding activity and translation-inhibition activity, UBE2N and UBE2E1 which negatively regulates their activity, IRF3 which inhibits its ubiquitination and degradation and FLNB which prevents its ability to interact with the upstream activators of the JNK cascade thereby inhibiting IFNA-induced JNK signaling. Exhibits antiviral activity towards both DNA and RNA viruses, including influenza A, HIV-1 and Ebola virus. Restricts HIV-1 and ebola virus via disruption of viral budding. Inhibits the ubiquitination of HIV-1 Gag and host TSG101 and disrupts their interaction, thereby preventing assembly and release of virions from infected cells. Inhibits Ebola virus budding mediated by the VP40 protein by disrupting ubiquitin ligase activity of NEDD4 and its ability to ubiquitinate VP40. ISGylates influenza A virus NS1 protein which causes a loss of function of the protein and the inhibition of virus replication. The secreted form of ISG15 can: induce natural killer cell proliferation, act as a chemotactic factor for neutrophils and act as a IFN-gamma-inducing cytokine playing an essential role in antimycobacterial immunity. The secreted form acts through the integrin ITGAL/ITGB2 receptor to initiate activation of SRC family tyrosine kinases including LYN, HCK and FGR which leads to secretion of IFNG and IL10; the interaction is mediated by ITGAL (PubMed:29100055).SUBUNIT Homodimer; disulfide-linked (PubMed:2440890). Interacts with, and is conjugated to its targets by UBE1L (E1 enzyme) and UBE2E2 (E2 enzyme) (PubMed:11157743, PubMed:15131269). Interacts with NEDD4 (PubMed:18305167).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein E3.SUBUNIT (Microbial infection) Interaction with influenza B NS1 protein inhibits its conjugation.TISSUE SPECIFICITY Detected in lymphoid cells, striated and smooth muscle, several epithelia and neurons. Expressed in neutrophils, monocytes and lymphocytes. Enhanced expression seen in pancreatic adenocarcinoma, endometrial cancer, and bladder cancer, as compared to non-cancerous tissue. In bladder cancer, the increase in expression exhibits a striking positive correlation with more advanced stages of the disease.INDUCTION Strongly induced upon exposure to type I interferons, viruses, LPS, and other stresses, including certain genotoxic stresses.DOMAIN Both the Ubiquitin-like 1 and Ubiquitin-like 2 domains are required for its efficient conjugation to cellular proteins. The two domains play different roles in the ISGylation pathway: Ubiquitin-like 2 domain is necessary for the first two steps allowing the linking of ISG15 to the E1 and E2 enzymes while Ubiquitin-like 1 domain is essential for the final, E3-mediated transfer of ISG15, from the E2 to the Lys of the target protein (PubMed:18356159).PTM S-nitrosylation decreases its dimerization, thereby increasing the availability as well as the solubility of monomeric ISG15 for its conjugation to cellular proteins.PTM Induced as an inactive, precursor protein that is cleaved by specific proteases to expose the C-terminal diglycine (LRLRGG) motif. This motif is essential not only for its conjugation to substrates but also for its recognition by the relevant processing proteases. UniProt P05161 157 EQUAL 2 EQUAL 157 EQUAL Reactome Database ID Release 78 5653745 Database 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=5653745 Reactome R-HSA-5653745 1 Reactome 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-5653745.1 1 K168-PCNA-G157-ISG15 Reactome DB_ID: 5653744 157 EQUAL 2 EQUAL 157 EQUAL Reactome Database ID Release 78 5653744 Database 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=5653744 Reactome R-HSA-5653744 1 Reactome 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-5653744.1 1 Reactome Database ID Release 78 5653767 Database 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=5653767 Reactome R-HSA-5653767 1 Reactome 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-5653767.1 1 Reactome Database ID Release 78 5653771 Database 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=5653771 Reactome R-HSA-5653771 1 Reactome 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-5653771.1 1 RPA heterotrimer Reactome DB_ID: 68462 RPA3 DNA Replication factor A protein 3 (14kD) RPA14 Replication protein A 14 kDa subunit RP-A RF-A Replication factor-A protein 3 Reactome DB_ID: 68459 UniProt:P35244 RPA3 RPA3 REPA3 RPA14 FUNCTION 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. 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. 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. RPA3 has its own single-stranded DNA-binding activity and may be responsible for polarity of the binding of the complex to DNA (PubMed:19010961). 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. 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.PTM 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).SIMILARITY Belongs to the replication factor A protein 3 family. UniProt P35244 1 EQUAL 121 EQUAL Reactome Database ID Release 78 68459 Database 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=68459 Reactome R-HSA-68459 2 Reactome 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-68459.2 1 RPA2 DNA Replication factor A protein 2 (32kD) RPA32 Replication protein A 32 kDa subunit RP-A RF-A Replication factor-A protein 2 Reactome DB_ID: 68457 UniProt:P15927 RPA2 RPA2 REPA2 RPA32 RPA34 FUNCTION 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. Thereby, it plays an essential role both in DNA replication and the cellular response to DNA damage. 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. It is required for the recruitment of the DNA double-strand break repair factors RAD51 and RAD52 to chromatin in response to DNA damage. 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. Plays also a role in base excision repair (BER) probably through interaction with UNG. Also recruits SMARCAL1/HARP, which is involved in replication fork restart, to sites of DNA damage. May also play a role in telomere maintenance.SUBUNIT Component of the replication protein A complex (RPA/RP-A), a heterotrimeric complex composed of RPA1, RPA2 and RPA3 (PubMed:2406247, PubMed:19116208, PubMed:10449415). 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 SERTAD3 (PubMed:10982866). Interacts with TIPIN (PubMed:17141802, PubMed:17296725). Interacts with TIMELESS (PubMed:17141802). Interacts with PPP4R2; the interaction is direct, DNA damage-dependent and mediates the recruitment of the PP4 catalytic subunit PPP4C (PubMed:20154705). Interacts (hyperphosphorylated) with RAD51 (PubMed:20154705). Interacts with SMARCAL1; the interaction is direct and mediates the recruitment to the RPA complex of SMARCAL1 (PubMed:19793861, PubMed:19793862, PubMed:19793863). Interacts with RAD52 and XPA; those interactions are direct and associate RAD52 and XPA to the RPA complex (PubMed:7700386, PubMed:8702565, PubMed:17765923, PubMed:11081631). Interacts with FBH1 (PubMed:23319600). Interacts with ETAA1; the interaction is direct and promotes ETAA1 recruitment at stalled replication forks (PubMed:27601467, PubMed:27723720, PubMed:27723717). Interacts with RFWD3 (PubMed:21504906, PubMed:21558276, PubMed:26474068, PubMed:28575657). Interacts with DDI2 (PubMed:29290612).INDUCTION Translationally up-regulated in response to DNA damage (at protein level).PTM Differentially phosphorylated throughout the cell cycle, becoming phosphorylated at the G1-S transition and dephosphorylated in late mitosis. Mainly phosphorylated at Ser-23 and Ser-29, by cyclin A-CDK2 and cyclin B-CDK1, respectively during DNA replication and mitosis. Dephosphorylation may require the serine/threonine-protein phosphatase 4. Phosphorylation at Ser-23 and Ser-29 is a prerequisite for further phosphorylation. Becomes hyperphosphorylated on additional residues including Ser-4, Ser-8, Thr-21 and Ser-33 in response to DNA damage. Hyperphosphorylation is mediated by ATM, ATR and PRKDC. Primarily recruited to DNA repair nuclear foci as a hypophosphorylated form it undergoes subsequent hyperphosphorylation, catalyzed by ATR. Hyperphosphorylation is required for RAD51 recruitment to chromatin and efficient DNA repair. Phosphorylation at Thr-21 depends upon RFWD3 presence.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).SIMILARITY Belongs to the replication factor A protein 2 family. UniProt P15927 1 EQUAL 270 EQUAL Reactome Database ID Release 78 68457 Database 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=68457 Reactome R-HSA-68457 2 Reactome 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-68457.2 1 RPA1 DNA Replication factor A protein A1 (70kD) RPA70 Replication protein A 70 kDa DNA-binding subunit RP-A RF-A Replication factor-A protein 1 Single-stranded DNA-binding protein Reactome DB_ID: 68461 UniProt:P27694 RPA1 RPA1 REPA1 RPA70 FUNCTION 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. UniProt P27694 2 EQUAL 616 EQUAL Reactome Database ID Release 78 68461 Database 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=68461 Reactome R-HSA-68461 2 Reactome 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-68461.2 1 Reactome Database ID Release 78 68462 Database 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=68462 Reactome R-HSA-68462 8 Reactome 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-68462.8 1 Reactome Database ID Release 78 5653772 Database 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=5653772 Reactome R-HSA-5653772 1 Reactome 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-5653772.1 1 USP43 Ubiquitin carboxyl-terminal hydrolase 43 Deubiquitinating enzyme 43 Ubiquitin thioesterase 43 Ubiquitin-specific-processing protease 43 Reactome DB_ID: 5653784 UniProt:Q70EL4 USP43 USP43 FUNCTION May recognize and hydrolyze the peptide bond at the C-terminal Gly of ubiquitin. Involved in the processing of poly-ubiquitin precursors as well as that of ubiquitinated proteins (By similarity).TISSUE SPECIFICITY Expressed in brain, aorta and lung at low levels.SIMILARITY Belongs to the peptidase C19 family. UniProt Q70EL4 1 EQUAL 1123 EQUAL Reactome Database ID Release 78 5653784 Database 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=5653784 Reactome R-HSA-5653784 1 Reactome 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-5653784.1 1 Reactome Database ID Release 78 5653781 Database 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=5653781 Reactome R-HSA-5653781 1 Reactome 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-5653781.1 ISG15 Interferon-induced 17 kDa protein component recommendedName: Ubiquitin cross-reactive protein UCRP_HUMAN Reactome DB_ID: 5653665 2 EQUAL 157 EQUAL Reactome Database ID Release 78 5653665 Database 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=5653665 Reactome R-HSA-5653665 1 Reactome 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-5653665.1 2 PCNA:RPA:RFC:TLS-DNA Template Reactome DB_ID: 5653782 1 1 PCNA homotrimer Reactome DB_ID: 68440 3 Reactome Database ID Release 78 68440 Database 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=68440 Reactome R-HSA-68440 1 Reactome 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-68440.1 ComplexPortal CPX-538 1 1 Reactome Database ID Release 78 5653782 Database 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=5653782 Reactome R-HSA-5653782 1 Reactome 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-5653782.1 ACTIVATION activeUnit: #Protein13 GENE ONTOLOGY GO:0019785 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 78 5653785 Database 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=5653785 Reactome Database ID Release 78 5653786 Database 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=5653786 Reactome R-HSA-5653786 1 Reactome 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-5653786.1 24768535 Pubmed 2014 Modification of PCNA by ISG15 plays a crucial role in termination of error-prone translesion DNA synthesis Park, Jung Mi Yang, Seung Wook Yu, Kyung Ryun Ka, Seung Hyun Lee, Seong Won Seol, Jae Hong Jeon, Young Joo Chung, Chin Ha Mol. Cell 54:626-38