BioPAX pathway converted from "Sensing of DNA Double Strand Breaks" in the Reactome database.Sensing of DNA Double Strand BreaksDetection of DNA double-strand breaks (DSBs) involves sensor proteins of the MRN complex, composed of MRE11A, RAD50 and NBN (NBS1). Binding of the MRN complex to DNA DSBs activates ATM-dependent DNA damage signaling cascade, by promoting KAT5 (Tip60) mediated acetylation of ATM and subsequent ATM autophosphorylation. Activated ATM triggers and coordinates recruitment of repair proteins to DNA DSBs (Beamish et al. 2002, Thompson and Schild 2002, Bakkenist et al. 2003, Lee and Paull 2005, Sun et al. 2005, Sun et al. 2007, Ciccia and Elledge 2010).Authored: Matthews, L, 2003-11-18 00:00:00Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12LEFT-TO-RIGHTFormation of RAD50:MRE11 complexMRE11 has both manganese dependent ssDNA 3'->5' exonuclease and endonuclease activities. MRE11 associates with RAD50, resulting in increased 3'-5' exonuclease activity (Dolganov et al. 1996, Paull and Gellert 1998).Authored: Matthews, L, 2003-08-11 05:43:00Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12MRE11ADouble-strand break repair protein MRE11AMRE11 homolog 1Reactome DB_ID: 59544nucleoplasmGENE ONTOLOGYGO:0005654UniProt:P49959 MRE11MRE11HNGS1MRE11AFUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11 (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). RAD50 may be required to bind DNA ends and hold them in close proximity (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289). This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:11741547, PubMed:29670289, PubMed:30612738). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).ACTIVITY REGULATION Interaction with SAMHD1 stimulates the double-strand-specific 3'-5' exonuclease activity.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:9651580, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with DCLRE1C/Artemis and DCLRE1B/Apollo (PubMed:15456891, PubMed:15723659, PubMed:18469862). Interacts with ATF2 (PubMed:15916964). Interacts with EXD2 (PubMed:26807646). Interacts with MRNIP (PubMed:27568553). Interacts with SAMHD1; leading to stimulate 3'-5' exonuclease activity (PubMed:28834754, PubMed:29670289). Interacts (when ubiquitinated) with UBQLN4 (via its UBA domain) (PubMed:30612738).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).PTM Ubiquitinated following DNA damage. Ubiquitination triggers interaction with UBQLN4, leading to MRE11 removal from chromatin and degradation by the proteasome.DISEASE Defects in MRE11 can be a cause of nephronophthisis-related ciliopathies (NPHP-RC), a group of recessive diseases that affect kidney, retina and brain. A homozygous truncating mutation MRE11 has been found in patients with cerebellar vermis hypoplasia, ataxia and dysarthria.MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the MRE11/RAD32 family.Homo sapiensNCBI Taxonomy9606UniProtP499591EQUAL708EQUALReactome Database ID Release 7559544Database 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=59544ReactomeR-HSA-595441Reactome 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-59544.1Reactomehttp://www.reactome.orgRAD50Reactome DB_ID: 75160UniProt:Q92878 RAD50RAD50FUNCTION Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. This could facilitate searches for short or long regions of sequence homology in the recombining DNA templates, and may also stimulate the activity of DNA ligases and/or restrict the nuclease activity of MRE11 to prevent nucleolytic degradation past a given point (PubMed:11741547, PubMed:9590181, PubMed:9705271, PubMed:9651580). The complex may also be required for DNA damage signaling via activation of the ATM kinase (PubMed:15064416). In telomeres the MRN complex may modulate t-loop formation (PubMed:10888888).SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:8756642, PubMed:9590181, PubMed:9705271, PubMed:10839544, PubMed:26215093). As part of the MRN complex, interacts with MCM8 and MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Found in a complex with TERF2 (PubMed:10888888). Interacts with RINT1 (PubMed:11096100). Interacts with BRCA1 via its N-terminal domain (PubMed:10426999). Interacts with DCLRE1C/Artemis (PubMed:15456891, PubMed:15723659). Interacts with MRNIP (PubMed:27568553).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12 (PubMed:20943970).TISSUE SPECIFICITY Expressed at very low level in most tissues, except in testis where it is expressed at higher level. Expressed in fibroblasts.DOMAIN The zinc-hook, which separates the large intramolecular coiled coil regions, contains 2 Cys residues that coordinate one molecule of zinc with the help of the 2 Cys residues of the zinc-hook of another RAD50 molecule, thereby forming a V-shaped homodimer. The two heads of the homodimer, which constitute the ATP-binding domain, interact with the MRE11 homodimer (By similarity).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.SIMILARITY Belongs to the SMC family. RAD50 subfamily.UniProtQ928781EQUAL1312EQUALReactome Database ID Release 7575160Database 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=75160ReactomeR-HSA-751601Reactome 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-75160.1RAD50:MRE11AReactome DB_ID: 7516111Reactome Database ID Release 7575161Database 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=75161ReactomeR-HSA-751612Reactome 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-75161.2Reactome Database ID Release 7575172Database 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=75172ReactomeR-HSA-751722Reactome 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-75172.28756642Pubmed1996Human Rad50 is physically associated with human Mre11: identification of a conserved multiprotein complex implicated in recombinational DNA repairDolganov, G MMaser, RSNovikov, ATosto, LChong, SBressan, D APetrini, JHMol. Cell. Biol. 16:4832-419651580Pubmed1998The 3' to 5' exonuclease activity of Mre 11 facilitates repair of DNA double-strand breaksPaull, TTGellert, MMol Cell 1:969-79LEFT-TO-RIGHTNBN binds KPNA2In the cytosol, NBN (NBS1) binds KPNA2, an importin alpha family member. The armadillo repeats of KPNA2 and a nuclear localization signal (NLS) of NBN are involved in the interaction (Tseng et al. 2005).Authored: Orlic-Milacic, Marija, 2015-05-12Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12IMA2KPNA2Reactome DB_ID: 205976cytosolGENE ONTOLOGYGO:0005829UniProt:P52292 KPNA2KPNA2RCH1SRP1FUNCTION Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus.SUBUNIT Heterodimer; with KPNB1 (PubMed:17596301). Interacts with ANP32E (By similarity). Component of a complex containing CSE1L, RAN and KPNA2. Interacts directly with CSE1L. Interacts with PLAG1. Interacts with APEX1 (via N-terminus). Interacts with FRG1 (via N-terminus). Interacts with ARL4A, CTNNBL1 and NBN. Interacts with SNAI1 (via zinc fingers) and SNAI2 (via zinc fingers). Interacts with BAG6 (PubMed:29042515). Interacts with AIFM2; this interaction likely mediates the translocation of AIFM2 into the nucleus upon oxidative stress.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpr.SUBUNIT (Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.SUBUNIT (Microbial infection) Interacts with SARS-COV virus ORF6 protein; this interaction blocks the receptor-mediated transport through the nuclear pore.TISSUE SPECIFICITY Expressed ubiquitously.DOMAIN Consists of an N-terminal hydrophilic region, a hydrophobic central region composed of 10 repeats, and a short hydrophilic C-terminus. The N-terminal hydrophilic region contains the importin beta binding domain (IBB domain), which is sufficient for binding importin beta and essential for nuclear protein import.DOMAIN The IBB domain is thought to act as an intrasteric autoregulatory sequence by interacting with the internal autoinhibitory NLS. Binding of KPNB1 probably overlaps the internal NLS and contributes to a high affinity for cytoplasmic NLS-containing cargo substrates. After dissociation of the importin/substrate complex in the nucleus the internal autohibitory NLS contributes to a low affinity for nuclear NLS-containing proteins (By similarity).DOMAIN The major and minor NLS binding sites are mainly involved in recognition of simple or bipartite NLS motifs. Structurally located within in a helical surface groove they contain several conserved Trp and Asn residues of the corresponding third helices (H3) of ARM repeats which mainly contribute to binding (By similarity).SIMILARITY Belongs to the importin alpha family.UniProtP522922EQUAL529EQUALReactome Database ID Release 75205976Database 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=205976ReactomeR-HSA-2059761Reactome 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-205976.1NBNNBS1Reactome DB_ID: 5684005UniProt:O60934 NBNNBNNBSNBS1P95FUNCTION Component of the MRE11-RAD50-NBN (MRN complex) which plays a critical role in the cellular response to DNA damage and the maintenance of chromosome integrity. The complex is involved in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity, cell cycle checkpoint control and meiosis. The complex possesses single-strand endonuclease activity and double-strand-specific 3'-5' exonuclease activity, which are provided by MRE11. RAD50 may be required to bind DNA ends and hold them in close proximity. NBN modulate the DNA damage signal sensing by recruiting PI3/PI4-kinase family members ATM, ATR, and probably DNA-PKcs to the DNA damage sites and activating their functions. It can also recruit MRE11 and RAD50 to the proximity of DSBs by an interaction with the histone H2AX. NBN also functions in telomere length maintenance by generating the 3' overhang which serves as a primer for telomerase dependent telomere elongation. NBN is a major player in the control of intra-S-phase checkpoint and there is some evidence that NBN is involved in G1 and G2 checkpoints. The roles of NBS1/MRN encompass DNA damage sensor, signal transducer, and effector, which enable cells to maintain DNA integrity and genomic stability. Forms a complex with RBBP8 to link DNA double-strand break sensing to resection. Enhances AKT1 phosphorylation possibly by association with the mTORC2 complex.SUBUNIT Component of the MRN complex composed of two heterodimers RAD50/MRE11 associated with a single NBN (PubMed:26215093, PubMed:9590181, PubMed:9705271, PubMed:11238951). As part of the MRN complex, interacts with MCM9; the interaction recruits the complex to DNA repair sites (PubMed:26215093). Component of the BASC complex, at least composed of BRCA1, MSH2, MSH6, MLH1, ATM, BLM, RAD50, MRE11 and NBN (PubMed:10783165). Interacts with histone H2AX this requires phosphorylation of H2AX on 'Ser-139' (PubMed:12419185). Interacts with HJURP (PubMed:17823411). Interacts with INTS3 (PubMed:19683501). Interacts with KPNA2 (PubMed:16188882). Interacts with TERF2 (PubMed:10888888). Interacts with RBBP8; the interaction links the role of the MRN complex in DNA double-strand break sensing to resection (PubMed:19759395). Interacts with SP100; recruits NBN to PML bodies (PubMed:12470659). Interacts with ATF2 (PubMed:15916964). Interacts with MTOR, MAPKAP1 isoform 2 and RICTOR; indicative for an association with the mTORC2 complex (PubMed:23762398). Interacts with MRNIP (PubMed:27568553). Interacts with UFL1; promoting UFL1 recruitment to double-strand breaks following DNA damage (PubMed:30886146).SUBUNIT (Microbial infection) Interacts with herpes simplex virus 1 protein UL12.TISSUE SPECIFICITY Ubiquitous. Expressed at high levels in testis.INDUCTION Up-regulated by ionizing radiation (IR).DOMAIN The FHA and BRCT domains are likely to have a crucial role for both binding to histone H2AX and for relocalization of MRE11/RAD50 complex to the vicinity of DNA damage.DOMAIN The C-terminal domain contains a MRE11-binding site, and this interaction is required for the nuclear localization of the MRN complex.DOMAIN The EEXXXDDL motif at the C-terminus is required for the interaction with ATM and its recruitment to sites of DNA damage and promote the phosphorylation of ATM substrates, leading to the events of DNA damage response.PTM Phosphorylated by ATM in response of ionizing radiation, and such phosphorylation is responsible intra-S phase checkpoint control and telomere maintenance.DISEASE Defects in NBN might play a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).MISCELLANEOUS In case of infection by adenovirus E4, the MRN complex is inactivated and degraded by viral oncoproteins, thereby preventing concatenation of viral genomes in infected cells.UniProtO609341EQUAL754EQUALReactome Database ID Release 755684005Database 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=5684005ReactomeR-HSA-56840051Reactome 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-5684005.1NBN:KPNA2Reactome DB_ID: 568401111Reactome Database ID Release 755684011Database 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=5684011ReactomeR-HSA-56840111Reactome 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-5684011.1Reactome Database ID Release 755684008Database 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=5684008ReactomeR-HSA-56840081Reactome 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-5684008.116188882Pubmed2005Importin KPNA2 is required for proper nuclear localization and multiple functions of NBS1Tseng, Shun-FuChang, Chun-YuWu, Kou-JueyTeng, Shu-ChunJ. Biol. Chem. 280:39594-600LEFT-TO-RIGHTKPNA2 translocates NBN to the nucleusKPNA2 facilitates the translocation of NBN (NBS1) to the nucleus, thereby making NBN available for the formation of MRN complexes in response to DNA double strand breaks (DSBs) (Tseng et al. 2005).Authored: Orlic-Milacic, Marija, 2015-05-12Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12NBNNBS1Reactome DB_ID: 751631EQUAL754EQUALReactome Database ID Release 7575163Database 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=75163ReactomeR-HSA-751631Reactome 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-75163.1IMA2KPNA2Reactome DB_ID: 2060452EQUAL529EQUALReactome Database ID Release 75206045Database 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=206045ReactomeR-HSA-2060451Reactome 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-206045.1Reactome Database ID Release 755684006Database 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=5684006ReactomeR-HSA-56840061Reactome 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-5684006.1LEFT-TO-RIGHTAssociation of RAD50:MRE11A complex with NBN (NBS1) via MRE11A interactionNBN (NBS1) binds MRE11A:RAD50 complex to form the evolutionarily conserved MRN complex (Trujillo et al. 1998). Authored: Lees-Miller, S, Thompson, L, 2003-07-14 15:03:24Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12MRNMRE11:RAD50:NBS1MRE11:RAD50:NBNReactome DB_ID: 75164111Reactome Database ID Release 7575164Database 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=75164ReactomeR-HSA-751641Reactome 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-75164.1ComplexPortalCPX-4442additional informationMIMI:0361Reactome Database ID Release 7575174Database 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=75174ReactomeR-HSA-751742Reactome 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-75174.29705271Pubmed1998Nuclease activities in a complex of human recombination and DNA repair factors Rad50, Mre11, and p95.Trujillo, KMYuan, SSLee, EYSung, PJ Biol Chem 273:21447-50LEFT-TO-RIGHTDSB inducing agents induce double strand DNA breaksReactive oxygen species (ROS) induce DNA double strand breaks (DSBs) (Yu and Anderson 1997) in cells undergoing oxidative stress. In addition to ROS, DSBs can also be directly generated by ionizing radiation. Agents that interfere with the progression of replication forks, such as topoisomerase poisons used in chemotherapy, induce DSBs indirectly (Curtin 2012). Authored: Orlic-Milacic, M, 2013-07-15Reviewed: Samarajiwa, Shamith, 2013-09-03Reviewed: Borowiec, James A, 2015-06-12Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15Edited: Orlic-Milacic, Marija, 2015-05-12dsDNADouble Strand DNAReactome DB_ID: 5649637Reactome Database ID Release 755649637Database 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=5649637ReactomeR-HSA-56496372Reactome 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-5649637.2ChEBI16991Converted from EntitySet in ReactomeDSB inducing agentsDouble strand break inducing agentsReactome DB_ID: 6783909ROSreactive oxygen speciesReactome DB_ID: 3785707reactive oxygen species [ChEBI:26523]reactive oxygen speciesChEBICHEBI:26523Reactome Database ID Release 753785707Database 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=3785707ReactomeR-ALL-37857073Reactome 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-3785707.3alpha-particlenucleus of the 4He atomReactome DB_ID: 6783905alpha-particle [ChEBI:30216]alpha-particlealpha(4)He(2+)ChEBICHEBI:30216Reactome Database ID Release 756783905Database 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=6783905ReactomeR-ALL-67839052Reactome 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-6783905.2protonReactome DB_ID: 6783901proton [ChEBI:24636]proton(1)H(+)p(+)(1)1H(+)pChEBICHEBI:24636Reactome Database ID Release 756783901Database 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=6783901ReactomeR-ALL-67839012Reactome 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-6783901.2e-beta-particleelectronReactome DB_ID: 6783907electron [ChEBI:10545]electronChEBICHEBI:10545Reactome Database ID Release 756783907Database 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=6783907ReactomeR-ALL-67839073Reactome 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-6783907.3X-rayphotonReactome DB_ID: 6783899photon [ChEBI:30212]photonhnuLichtquantLightgammalight quantumfotonChEBICHEBI:30212Reactome Database ID Release 756783899Database 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=6783899ReactomeR-ALL-67838993Reactome 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-6783899.3photongamma-rayReactome DB_ID: 6783900Reactome Database ID Release 756783900Database 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=6783900ReactomeR-ALL-67839003Reactome 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-6783900.3Reactome Database ID Release 756783909Database 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=6783909ReactomeR-ALL-67839091Reactome 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-6783909.1DNA double-strand break endsReactome DB_ID: 75165Reactome Database ID Release 7575165Database 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=75165ReactomeR-ALL-751652Reactome 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-75165.2ChEBI61120Reactome Database ID Release 753785704Database 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=3785704ReactomeR-HSA-37857042Reactome 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-3785704.223175119Pubmed2012DNA repair dysregulation from cancer driver to therapeutic targetCurtin, Nicola JNat. Rev. Cancer 12:801-179357549Pubmed1997Reactive oxygen species-induced DNA damage and its modification: a chemical investigationYu, T WAnderson, DMutat. Res. 379:201-10LEFT-TO-RIGHTMRN complex binds DNA double strand breaksThe MRN complex (MRE11A:RAD50:NBN) binds to DNA ends found at double strand breaks (DNA DSBs) (Lee and Paull 2005). In budding yeast, the Mre11:Rad50:Xrs2 complex, homologous to human MRN, rapidly localizes to DNA breaks (Shroff et al. 2004, Lisby et al. 2004).Authored: Orlic-Milacic, M, 2013-07-15Reviewed: Samarajiwa, Shamith, 2013-09-03Reviewed: Borowiec, James A, 2015-06-12Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15DNA DSBs:MRNReactome DB_ID: 378576311Reactome Database ID Release 753785763Database 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=3785763ReactomeR-HSA-37857631Reactome 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-3785763.1ComplexPortalCPX-4442Reactome Database ID Release 753785768Database 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=3785768ReactomeR-HSA-37857682Reactome 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-3785768.215790808Pubmed2005ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complexLee, JHPaull, TTScience 308:551-415369670Pubmed2004Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteinsLisby, MichaelBarlow, Jacqueline HBurgess, Rebecca CRothstein, RodneyCell 118:699-71315458641Pubmed2004Distribution and dynamics of chromatin modification induced by a defined DNA double-strand breakShroff, RobertArbel-Eden, AyeletPilch, DuaneIra, GrzegorzBonner, WMPetrini, John HHaber, James ELichten, MichaelCurr. Biol. 14:1703-11LEFT-TO-RIGHTMRN complex bound to DNA ends recruits ATMActivation of ATM kinase in response to DNA damage in the form of DNA double strand breaks (DSBs) requires association of ATM dimers with the MRN complex bound to DNA ends. MRN subunit RAD50 is essential for ATM dimer binding (Lee and Paull 2005, Wu et al. 2007). ATM dimer exists in a preformed complex with KAT5 (Tip60) histone acetyltransferase (Sun et al. 2005).Authored: Orlic-Milacic, M, 2013-07-15Reviewed: Samarajiwa, Shamith, 2013-09-03Reviewed: Borowiec, James A, 2015-06-12Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15Edited: Orlic-Milacic, Marija, 2015-05-12ATM dimer:KAT5ATM dimer:Tip60Reactome DB_ID: 5682037dimeric ATM kinaseReactome DB_ID: 83538ATMATM serine-protein kinaseSerine-protein kinase ATM (EC 2.7.1.37) (Ataxia telangiectasia mutated) (A-T, mutated)Serine-protein kinase ATM Ataxia telangiectasia mutatedA-T, mutatedReactome DB_ID: 69484UniProt:Q13315 ATMATMFUNCTION Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, UFL1, RAD9, UBQLN4 and DCLRE1C (PubMed:9843217, PubMed:9733515, PubMed:10550055, PubMed:10766245, PubMed:10839545, PubMed:10910365, PubMed:10802669, PubMed:10973490, PubMed:11375976, PubMed:12086603, PubMed:15456891, PubMed:19965871, PubMed:30612738, PubMed:30886146). May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response. Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).ACTIVITY REGULATION Inhibited by wortmannin.SUBUNIT Homodimer (PubMed:28508083). Dimers or tetramers in inactive state. On DNA damage, autophosphorylation dissociates ATM into monomers rendering them catalytically active. Binds p53/TP53, ABL1, BRCA1, NBN/nibrin and TERF1. Part of the BRCA1-associated genome surveillance complex (BASC), which contains BRCA1, MSH2, MSH6, MLH1, ATM, BLM, PMS2 and the RAD50-MRE11-NBN protein complex. This association could be a dynamic process changing throughout the cell cycle and within subnuclear domains. Interacts with RAD17; DNA damage promotes the association. Interacts with EEF1E1; the interaction, induced on DNA damage, up-regulates TP53. Interacts with DCLRE1C, KAT8, KAT5, NABP2, ATMIN and CEP164. Interacts with AP2B1 and AP3B2; the interaction occurs in cytoplasmic vesicles (By similarity). Interacts with TELO2 and TTI1. Interacts with DDX1. Interacts with BRAT1.TISSUE SPECIFICITY Found in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain, heart, spleen, thymus, testis, ovary, small intestine, colon and leukocytes.INDUCTION By ionizing radiation.DOMAIN The FATC domain is required for interaction with KAT5.PTM Phosphorylated by NUAK1/ARK5 (PubMed:12409306). Autophosphorylation on Ser-367, Ser-1893, Ser-1981 correlates with DNA damage-mediated activation of the kinase (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:21144835, PubMed:27664052). During the late stages of DNA damage response, dephosphorylated following deacetylation by SIRT7, leading to ATM deactivation (PubMed:30944854).PTM Acetylation, on DNA damage, is required for activation of the kinase activity, dimer-monomer transition, and subsequent autophosphorylation on Ser-1981 (PubMed:12556884, PubMed:16141325, PubMed:16858402, PubMed:17923702, PubMed:21144835). Acetylated in vitro by KAT5/TIP60 (PubMed:16141325). Deacetylated by SIRT7 during the late stages of DNA damage response, promoting ATM dephosphorylation and subsequent deactivation (PubMed:30944854).DISEASE Defects in ATM may contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.DISEASE Defects in ATM may contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).DISEASE Defects in ATM may contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.SIMILARITY Belongs to the PI3/PI4-kinase family. ATM subfamily.UniProtQ133151EQUAL3056EQUALReactome Database ID Release 7569484Database 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=69484ReactomeR-HSA-694841Reactome 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-69484.12Reactome Database ID Release 7583538Database 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=83538ReactomeR-HSA-835381Reactome 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-83538.11KAT5Histone acetyltransferase KAT5KAT5_HUMANTip60Reactome DB_ID: 3321979UniProt:Q92993 KAT5KAT5HTATIPTIP60FUNCTION Catalytic subunit of the NuA4 histone acetyltransferase complex which is involved in transcriptional activation of select genes principally by acetylation of nucleosomal histones H4 and H2A (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:16387653, PubMed:19909775, PubMed:15196461). This modification may both alter nucleosome-DNA interactions and promote interaction of the modified histones with other proteins which positively regulate transcription (PubMed:12776177, PubMed:15042092, PubMed:15121871, PubMed:15310756, PubMed:14966270, PubMed:15196461). This complex may be required for the activation of transcriptional programs associated with oncogene and proto-oncogene mediated growth induction, tumor suppressor mediated growth arrest and replicative senescence, apoptosis, and DNA repair (PubMed:15196461). NuA4 may also play a direct role in DNA repair when recruited to sites of DNA damage (PubMed:15196461). Component of a SWR1-like complex that specifically mediates the removal of histone H2A.Z/H2AZ1 from the nucleosome (PubMed:24463511). Also acetylates non-histone proteins, such as ATM, NR1D2, RAN, FOXP3, ULK1 and RUBCNL/Pacer (PubMed:16141325, PubMed:17360565, PubMed:17996965, PubMed:29040603, PubMed:30704899). Directly acetylates and activates ATM (PubMed:16141325). Relieves NR1D2-mediated inhibition of APOC3 expression by acetylating NR1D2 (PubMed:17996965). Promotes FOXP3 acetylation and positively regulates its transcriptional repressor activity (PubMed:17360565). Acetylates RAN at 'Lys-134' (PubMed:29040603). Together with GSK3 (GSK3A or GSK3B), acts as a regulator of autophagy: phosphorylated at Ser-86 by GSK3 under starvation conditions, leading to activate acetyltransferase activity and promote acetylation of key autophagy regulators, such as ULK1 and RUBCNL/Pacer (PubMed:30704899).ACTIVITY REGULATION Acetyltransferase activity is promoted by phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B).SUBUNIT Component of the NuA4 histone acetyltransferase complex which contains the catalytic subunit KAT5/TIP60 and the subunits EP400, TRRAP/PAF400, BRD8/SMAP, EPC1, DMAP1/DNMAP1, RUVBL1/TIP49, RUVBL2, ING3, actin, ACTL6A/BAF53A, MORF4L1/MRG15, MORF4L2/MRGX, MRGBP, YEATS4/GAS41, VPS72/YL1 and MEAF6 (PubMed:12963728, PubMed:10966108, PubMed:15196461, PubMed:14966270). HTATTIP/TIP60, EPC1, and ING3 together constitute a minimal HAT complex termed Piccolo NuA4. The NuA4 complex interacts with MYC. Interacts with ATM (PubMed:16141325). Interacts with JADE1 (PubMed:15502158). Interacts with PLA2G4A/CPLA2, EDNRA and HDAC7 (PubMed:11416127, PubMed:11262386, PubMed:12551922). Interacts with the cytoplasmic tail of APP and APBB1/FE65 (By similarity). Interacts with TRIM24 and TRIM68 (PubMed:18451177, PubMed:19909775). Forms a complex with SENP6 and UBE2I in response to UV irradiation. Identified in a complex with HINT1 (PubMed:16835243). Interacts with ATF2 and CUL3 (PubMed:18397884). Interacts with NR1D2 (via N-terminus) (PubMed:17996965). Component of a SWR1-like complex (PubMed:24463511). Interacts with FOXP3 (PubMed:17360565). Interacts with ZBTB49 (PubMed:25245946).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT.PTM (Microbial infection) In case of HIV-1 infection, interaction with the viral Tat protein leads to KAT5 polyubiquitination and targets it to degradation.PTM Sumoylated by UBE2I at Lys-430 and Lys-451, leading to increase of its histone acetyltransferase activity in UV-induced DNA damage response, as well as its translocation to nuclear bodies.PTM Ubiquitinated by MDM2, leading to its proteasome-dependent degradation.PTM Phosphorylated on Ser-86 and Ser-90; enhanced during G2/M phase (PubMed:12468530). The phosphorylated form has a higher histone acetyltransferase activity (PubMed:12468530). Phosphorylation at Ser-86 by GSK3 (GSK3A or GSK3B) activates acetyltransferase activity (PubMed:30704899). Phosphorylation at Ser-90 is a prerequisite for phosphorylation at Ser-86 by GSK3 (PubMed:30704899).PTM Autoacetylation at Lys-327 is required for proper function.SIMILARITY Belongs to the MYST (SAS/MOZ) family.UniProtQ929931EQUAL513EQUALReactome Database ID Release 753321979Database 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=3321979ReactomeR-HSA-33219791Reactome 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-3321979.11Reactome Database ID Release 755682037Database 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=5682037ReactomeR-HSA-56820371Reactome 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-5682037.1DNA DSBs:MRN:ATM dimer:KAT5Reactome DB_ID: 3785779111Reactome Database ID Release 753785779Database 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=3785779ReactomeR-HSA-37857792Reactome 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-3785779.2Reactome Database ID Release 755693612Database 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=5693612ReactomeR-HSA-56936121Reactome 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-5693612.116141325Pubmed2005A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATMSun, YingliJiang, XiaofengChen, ShujuanFernandes, NorvinPrice, Brendan DProc. Natl. Acad. Sci. U.S.A. 102:13182-717694070Pubmed2007MRE11-RAD50-NBS1 and ATM function as co-mediators of TRF1 in telomere length controlWu, YiliXiao, ShujieZhu, Xu-DongNat. Struct. Mol. Biol. 14:832-40LEFT-TO-RIGHT2.3.1KAT5 acetylates ATM at DNA DSBsThe histone acetyltransferase Tip60 (KAT5), in addition to forming a histone acetyltransferase complex with NuA4, forms another complex with ATM dimers. The ATM dimer:KAT5 complex is formed in the absence of DNA damage, but the acetyltransferase activity of KAT5 is activated by double strand DNA breaks (DNA DSBs) (Sun et al. 2005). In response to DNA DSBs, the MRN complex targets KAT5 to chromatin, where KAT5 associates with histone H3 trimethylated on lysine 10 (commonly known as H3K9me3 mark). Besides the MRN complex, the ability of KAT5 to access H3K9me3 depends on the DNA damage-induced displacement of HP1beta (CBX1) from H3K9me3 (Ayoub et al. 2008). Binding to H3K9me3 activates the acetyltransferase activity of KAT5 (Sun et al. 2009). KAT5 acetylates ATM on lysine residue K3016 in the highly conserved C-terminal FATC domain of ATM. ATM acetylation is needed for the activation of ATM kinase activity in response to DNA damage (Sun et al. 2007). Authored: Orlic-Milacic, Marija, 2015-05-12Reviewed: Borowiec, James A, 2015-06-12Edited: Orlic-Milacic, Marija, 2015-05-12Ac-CoAAcetyl coenzyme Aacetyl-CoAReactome DB_ID: 113560acetyl-CoA [ChEBI:15351]acetyl-CoAChEBICHEBI:15351Reactome Database ID Release 75113560Database 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=113560ReactomeR-ALL-1135603Reactome 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-113560.3COMPOUNDC000242DNA DSBs:MRN:Ac-K3016-ATM dimer:KAT5Reactome DB_ID: 5682035Ac-K3016-ATM dimerAcetylated ATM dimerReactome DB_ID: 5682046Ac-K3016-ATMReactome DB_ID: 56820433016EQUALN6-acetyl-L-lysineMODMOD:000641EQUAL3056EQUALReactome Database ID Release 755682043Database 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=5682043ReactomeR-HSA-56820431Reactome 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-5682043.12Reactome Database ID Release 755682046Database 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=5682046ReactomeR-HSA-56820461Reactome 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-5682046.1111Reactome Database ID Release 755682035Database 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=5682035ReactomeR-HSA-56820351Reactome 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-5682035.1CoACoA-SHcoenzyme AReactome DB_ID: 2485002coenzyme A [ChEBI:15346]coenzyme AChEBICHEBI:15346Reactome Database ID Release 752485002Database 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=2485002ReactomeR-ALL-24850023Reactome 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-2485002.3COMPOUNDC000102ACTIVATIONactiveUnit: #Protein8GENE ONTOLOGYGO:0016407gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 755682030Database 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=5682030Reactome Database ID Release 755682044Database 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=5682044ReactomeR-HSA-56820441Reactome 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-5682044.117923702Pubmed2007DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activitySun, YingliXu, YeRoy, KanaklataPrice, Brendan DMol. Cell. Biol. 27:8502-919783983Pubmed2009Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60Sun, YingliJiang, XiaofengXu, YeAyrapetov, Marina KMoreau, Lisa AWhetstine, Johnathan RPrice, Brendan DNat. Cell Biol. 11:1376-8218438399Pubmed2008HP1-beta mobilization promotes chromatin changes that initiate the DNA damage responseAyoub, NabiehJeyasekharan, Anand DBernal, Juan AVenkitaraman, Ashok RNature 453:682-6LEFT-TO-RIGHT2.7.11MRN activates ATMMRN promotes dissociation of ATM dimers to ATM monomers which is accompanied by ATM trans-autophosphorylation on serine residue S1981 (Bakkenist et al. 2003, Du et al. 2014). ATM autophosphorylation at serine residues S367 and S1893 is also implicated in ATM activation (Kozlov et al. 2006). Dissociation of ATM dimers requires the ATP-dependent DNA-helicase activity of the MRN subunit RAD50 (Lee and Paull 2005). KAT5 (Tip60) mediated acetylation of ATM dimers at lysine K3016 is a prerequisite for ATM kinase activity (Sun et al. 2007). Upon the dissociation of ATM dimers induced by DNA double strand breaks (DSBs), a fraction of activated ATM is retained at DSB sites, co-localizing with the MRN complex (Andegeko et al. 2001, Uziel et al. 2003) at ionizing radiation-induced foci (IRIF). MRN facilitates the binding of a portion of ATM substrates to ATM (Lee and Paull 2004).<p>After the DNA double strand breaks (DSBs) are repaired, ATM is dephosphorylated by an unidentified PP2A phosphatase complex, leading to dimer reformation (Goodarzi et al. 2004).Authored: Orlic-Milacic, M, 2013-07-15Reviewed: Samarajiwa, Shamith, 2013-09-03Reviewed: Borowiec, James A, 2015-06-12Edited: D'Eustachio, P, 2013-07-15Edited: Matthews, L, 2013-07-15Edited: Orlic-Milacic, Marija, 2015-05-12ATPAdenosine 5'-triphosphateATP(4-)Reactome DB_ID: 29358ATP(4-) [ChEBI:30616]ATP(4-)ATPatpAdenosine 5'-triphosphateChEBICHEBI:30616Reactome Database ID Release 7529358Database 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=29358ReactomeR-ALL-293583Reactome 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-29358.3COMPOUNDC000022p-S1981,Ac-K3016-ATMReactome DB_ID: 56935271981EQUALO-phospho-L-serineMODMOD:000461EQUAL3056EQUALReactome Database ID Release 755693527Database 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=5693527ReactomeR-HSA-56935271Reactome 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-5693527.1DNA DSBs:MRN:p-S1981,Ac-K3016-ATM:KAT5Reactome DB_ID: 5682055111Reactome Database ID Release 755682055Database 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=5682055ReactomeR-HSA-56820551Reactome 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-5682055.1ADPAdenosine 5'-diphosphateADP(3-)Reactome DB_ID: 113582ADP(3-) [ChEBI:456216]ADP(3-)ADP5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADP trianionChEBICHEBI:456216Reactome Database ID Release 75113582Database 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=113582ReactomeR-ALL-1135823Reactome 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-113582.3COMPOUNDC000082ACTIVATIONactiveUnit: #Complex9GENE ONTOLOGYGO:0004674Reactome Database ID Release 755694649Database 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=5694649Reactome Database ID Release 755693540Database 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=5693540ReactomeR-HSA-56935401Reactome 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-5693540.125240135Pubmed2014Dimer monomer transition and dimer re-formation play important role for ATM cellular function during DNA repairDu, FengxiaZhang, MinjieLi, XiaohuaYang, CaiyunMeng, HaoWang, DongChang, ShuangXu, YePrice, BrendanSun, YingliBiochem. Biophys. Res. Commun. 452:1034-912556884Pubmed2003DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociationBakkenist, CJKastan, MBNature 421:499-50616858402Pubmed2006Involvement of novel autophosphorylation sites in ATM activationKozlov, Sergei VGraham, MEPeng, CChen, PRobinson, PJLavin, Martin FEMBO J. 25:3504-1411454856Pubmed2001Nuclear retention of ATM at sites of DNA double strand breaksAndegeko, YMoyal, LMittelman, LTsarfaty, IShiloh, YRotman, GJ. Biol. Chem. 276:38224-3014532133Pubmed2003Requirement of the MRN complex for ATM activation by DNA damage.Uziel, TLerenthal, YMoyal, LAndegeko, YMittelman, LShiloh, YEMBO J 22:5612-2115064416Pubmed2004Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complexLee, Ji-HoonPaull, Tanya TScience 304:93-615510216Pubmed2004Autophosphorylation of ataxia-telangiectasia mutated is regulated by protein phosphatase 2AGoodarzi, AAJonnalagadda, Jyoti CDouglas, PYoung, DavidYe, RuiqiongMoorhead, Greg B GLees-Miller, Susan PKhanna, Kum KumEMBO J. 23:4451-61Reactome Database ID Release 755693548Database 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=5693548ReactomeR-HSA-56935481Reactome 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-5693548.120965415Pubmed2010The DNA damage response: making it safe to play with knivesCiccia, AlbertoElledge, Stephen JMol. Cell 40:179-20412034743Pubmed2002Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM.Beamish, HKedar, PKaneko, HChen, PFukao, TPeng, CBeresten, SGueven, NPurdie, DLees-Miller, SEllis, NKondo, NLavin, MFJ Biol Chem 277:30515-2312427531Pubmed2002Recombinational DNA repair and human disease.Thompson, LHSchild, DMutat Res 509:49-78