ID H2AX_HUMAN Reviewed; 143 AA. AC P16104; Q4ZGJ7; Q6IAS5; DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot. DT 23-JAN-2007, sequence version 2. DT 07-APR-2021, entry version 215. DE RecName: Full=Histone H2AX; DE Short=H2a/x; DE AltName: Full=Histone H2A.X; GN Name=H2AX {ECO:0000312|HGNC:HGNC:4739}; GN Synonyms=H2AFX {ECO:0000312|HGNC:HGNC:4739}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=2587254; DOI=10.1093/nar/17.22.9113; RA Mannironi C., Bonner W.M., Hatch C.L.; RT "H2A.X. a histone isoprotein with a conserved C-terminal sequence, is RT encoded by a novel mRNA with both DNA replication type and polyA 3' RT processing signals."; RL Nucleic Acids Res. 17:9113-9126(1989). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG NIEHS SNPs program; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung, and Placenta; RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [5] RP PHOSPHORYLATION AT SER-140, AND MUTAGENESIS OF GLN-141. RX PubMed=9488723; DOI=10.1074/jbc.273.10.5858; RA Rogakou E.P., Pilch D.R., Orr A.H., Ivanova V.S., Bonner W.M.; RT "DNA double-stranded breaks induce histone H2AX phosphorylation on serine RT 139."; RL J. Biol. Chem. 273:5858-5868(1998). RN [6] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=10477747; DOI=10.1083/jcb.146.5.905; RA Rogakou E.P., Boon C., Redon C., Bonner W.M.; RT "Megabase chromatin domains involved in DNA double-strand breaks in vivo."; RL J. Cell Biol. 146:905-916(1999). RN [7] RP FUNCTION, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=10959836; DOI=10.1016/s0960-9822(00)00610-2; RA Paull T.T., Rogakou E.P., Yamazaki V., Kirchgessner C.U., Gellert M., RA Bonner W.M.; RT "A critical role for histone H2AX in recruitment of repair factors to RT nuclear foci after DNA damage."; RL Curr. Biol. 10:886-895(2000). RN [8] RP PHOSPHORYLATION AT SER-140. RX PubMed=10734083; DOI=10.1074/jbc.275.13.9390; RA Rogakou E.P., Nieves-Neira W., Boon C., Pommier Y., Bonner W.M.; RT "Initiation of DNA fragmentation during apoptosis induces phosphorylation RT of H2AX histone at serine 139."; RL J. Biol. Chem. 275:9390-9395(2000). RN [9] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=11673449; DOI=10.1074/jbc.c100569200; RA Ward I.M., Chen J.; RT "Histone H2AX is phosphorylated in an ATR-dependent manner in response to RT replicational stress."; RL J. Biol. Chem. 276:47759-47762(2001). RN [10] RP FUNCTION, INTERACTION WITH NBN AND BRCA1, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT SER-140. RX PubMed=12419185; DOI=10.1016/s0960-9822(02)01259-9; RA Kobayashi J., Tauchi H., Sakamoto S., Nakamura A., Morishima K., RA Matsuura S., Kobayashi T., Tamai K., Tanimoto K., Komatsu K.; RT "NBS1 localizes to gamma-H2AX foci through interaction with the FHA/BRCT RT domain."; RL Curr. Biol. 12:1846-1851(2002). RN [11] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=12697768; DOI=10.1074/jbc.c300117200; RA Ward I.M., Minn K., Jorda K.G., Chen J.; RT "Accumulation of checkpoint protein 53BP1 at DNA breaks involves its RT binding to phosphorylated histone H2AX."; RL J. Biol. Chem. 278:19579-19582(2003). RN [12] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=12660252; DOI=10.1074/jbc.m300198200; RA Furuta T., Takemura H., Liao Z.-Y., Aune G.J., Redon C., Sedelnikova O.A., RA Pilch D.R., Rogakou E.P., Celeste A., Chen H.T., Nussenzweig A., RA Aladjem M.I., Bonner W.M., Pommier Y.; RT "Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 RT in response to replication-dependent DNA double-strand breaks induced by RT mammalian DNA topoisomerase I cleavage complexes."; RL J. Biol. Chem. 278:20303-20312(2003). RN [13] RP FUNCTION, INTERACTION WITH MDC1 AND TP53BP1, SUBCELLULAR LOCATION, AND RP PHOSPHORYLATION AT SER-140. RX PubMed=12607005; DOI=10.1038/nature01446; RA Stewart G.S., Wang B., Bignell C.R., Taylor A.M.R., Elledge S.J.; RT "MDC1 is a mediator of the mammalian DNA damage checkpoint."; RL Nature 421:961-966(2003). RN [14] RP PHOSPHORYLATION AT SER-140. RX PubMed=14627815; DOI=10.1093/nar/gkg921; RA Park E.-J., Chan D.W., Park J.-H., Oettinger M.A., Kwon J.; RT "DNA-PK is activated by nucleosomes and phosphorylates H2AX within the RT nucleosomes in an acetylation-dependent manner."; RL Nucleic Acids Res. 31:6819-6827(2003). RN [15] RP SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT SER-140. RX PubMed=15059890; DOI=10.1158/0008-5472.can-03-3207; RA Stiff T., O'Driscoll M., Rief N., Iwabuchi K., Loebrich M., Jeggo P.A.; RT "ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure RT to ionizing radiation."; RL Cancer Res. 64:2390-2396(2004). RN [16] RP FUNCTION, INTERACTION WITH MDC1 AND NBN, AND SUBCELLULAR LOCATION. RX PubMed=15201865; DOI=10.1038/sj.emboj.7600269; RA Lukas C., Melander F., Stucki M., Falck J., Bekker-Jensen S., Goldberg M., RA Lerenthal Y., Jackson S.P., Bartek J., Lukas J.; RT "Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX- RT dependent chromatin retention."; RL EMBO J. 23:2674-2683(2004). RN [17] RP PHOSPHORYLATION AT SER-140. RX PubMed=15489221; DOI=10.1074/jbc.m406879200; RA Kurz E.U., Douglas P., Lees-Miller S.P.; RT "Doxorubicin activates ATM-dependent phosphorylation of multiple downstream RT targets in part through the generation of reactive oxygen species."; RL J. Biol. Chem. 279:53272-53281(2004). RN [18] RP INTERACTION WITH DHX9, SUBCELLULAR LOCATION, AND PHOSPHORYLATION AT RP SER-140. RX PubMed=15613478; DOI=10.1074/jbc.m411444200; RA Mischo H.E., Hemmerich P., Grosse F., Zhang S.; RT "Actinomycin D induces histone gamma-H2AX foci and complex formation of RT gamma-H2AX with Ku70 and nuclear DNA helicase II."; RL J. Biol. Chem. 280:9586-9594(2005). RN [19] RP DEPHOSPHORYLATION. RX PubMed=16310392; DOI=10.1016/j.molcel.2005.10.003; RA Chowdhury D., Keogh M.-C., Ishii H., Peterson C.L., Buratowski S., RA Lieberman J.; RT "gamma-H2AX dephosphorylation by protein phosphatase 2A facilitates DNA RT double-strand break repair."; RL Mol. Cell 20:801-809(2005). RN [20] RP INTERACTION WITH ARRB2. RX PubMed=16820410; DOI=10.1242/jcs.03046; RA Neuhaus E.M., Mashukova A., Barbour J., Wolters D., Hatt H.; RT "Novel function of beta-arrestin2 in the nucleus of mature spermatozoa."; RL J. Cell Sci. 119:3047-3056(2006). RN [21] RP UBIQUITINATION. RX PubMed=18001824; DOI=10.1016/j.cell.2007.09.040; RA Mailand N., Bekker-Jensen S., Faustrup H., Melander F., Bartek J., RA Lukas C., Lukas J.; RT "RNF8 ubiquitylates histones at DNA double-strand breaks and promotes RT assembly of repair proteins."; RL Cell 131:887-900(2007). RN [22] RP UBIQUITINATION. RX PubMed=18001825; DOI=10.1016/j.cell.2007.09.041; RA Huen M.S.Y., Grant R., Manke I., Minn K., Yu X., Yaffe M.B., Chen J.; RT "RNF8 transduces the DNA-damage signal via histone ubiquitylation and RT checkpoint protein assembly."; RL Cell 131:901-914(2007). RN [23] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Embryonic kidney; RX PubMed=17525332; DOI=10.1126/science.1140321; RA Matsuoka S., Ballif B.A., Smogorzewska A., McDonald E.R. III, Hurov K.E., RA Luo J., Bakalarski C.E., Zhao Z., Solimini N., Lerenthal Y., Shiloh Y., RA Gygi S.P., Elledge S.J.; RT "ATM and ATR substrate analysis reveals extensive protein networks RT responsive to DNA damage."; RL Science 316:1160-1166(2007). RN [24] RP UBIQUITINATION. RX PubMed=19203578; DOI=10.1016/j.cell.2008.12.042; RA Stewart G.S., Panier S., Townsend K., Al-Hakim A.K., Kolas N.K., RA Miller E.S., Nakada S., Ylanko J., Olivarius S., Mendez M., Oldreive C., RA Wildenhain J., Tagliaferro A., Pelletier L., Taubenheim N., Durandy A., RA Byrd P.J., Stankovic T., Taylor A.M.R., Durocher D.; RT "The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling RT cascade at sites of DNA damage."; RL Cell 136:420-434(2009). RN [25] RP UBIQUITINATION. RX PubMed=19203579; DOI=10.1016/j.cell.2008.12.041; RA Doil C., Mailand N., Bekker-Jensen S., Menard P., Larsen D.H., RA Pepperkok R., Ellenberg J., Panier S., Durocher D., Bartek J., Lukas J., RA Lukas C.; RT "RNF168 binds and amplifies ubiquitin conjugates on damaged chromosomes to RT allow accumulation of repair proteins."; RL Cell 136:435-446(2009). RN [26] RP PHOSPHORYLATION AT TYR-143, AND MUTAGENESIS OF TYR-143. RX PubMed=19092802; DOI=10.1038/nature07668; RA Xiao A., Li H., Shechter D., Ahn S.H., Fabrizio L.A., Erdjument-Bromage H., RA Ishibe-Murakami S., Wang B., Tempst P., Hofmann K., Patel D.J., RA Elledge S.J., Allis C.D.; RT "WSTF regulates the H2A.X DNA damage response via a novel tyrosine kinase RT activity."; RL Nature 457:57-62(2009). RN [27] RP PHOSPHORYLATION AT TYR-143, AND MUTAGENESIS OF TYR-143. RX PubMed=19234442; DOI=10.1038/nature07849; RA Cook P.J., Ju B.G., Telese F., Wang X., Glass C.K., Rosenfeld M.G.; RT "Tyrosine dephosphorylation of H2AX modulates apoptosis and survival RT decisions."; RL Nature 458:591-596(2009). RN [28] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Cervix carcinoma; RX PubMed=20068231; DOI=10.1126/scisignal.2000475; RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.; RT "Quantitative phosphoproteomics reveals widespread full phosphorylation RT site occupancy during mitosis."; RL Sci. Signal. 3:RA3-RA3(2010). RN [29] RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-140, AND IDENTIFICATION BY RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21406692; DOI=10.1126/scisignal.2001570; RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T., RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.; RT "System-wide temporal characterization of the proteome and phosphoproteome RT of human embryonic stem cell differentiation."; RL Sci. Signal. 4:RS3-RS3(2011). RN [30] RP UBIQUITINATION AT LYS-14 AND LYS-16 BY RNF168. RX PubMed=22980979; DOI=10.1016/j.cell.2012.08.005; RA Mattiroli F., Vissers J.H., van Dijk W.J., Ikpa P., Citterio E., RA Vermeulen W., Marteijn J.A., Sixma T.K.; RT "RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA Damage signaling."; RL Cell 150:1182-1195(2012). RN [31] RP INTERACTION WITH EPSTEIN-BARR VIRUS PROTEIN EBNA6 (MICROBIAL INFECTION), RP AND SUBCELLULAR LOCATION. RX PubMed=24429368; DOI=10.1128/jvi.03568-13; RA Jha H.C., Aj M.P., Saha A., Banerjee S., Lu J., Robertson E.S.; RT "Epstein-Barr virus essential antigen EBNA3C attenuates H2AX expression."; RL J. Virol. 88:3776-3788(2014). RN [32] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-135, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25218447; DOI=10.1038/nsmb.2890; RA Hendriks I.A., D'Souza R.C., Yang B., Verlaan-de Vries M., Mann M., RA Vertegaal A.C.; RT "Uncovering global SUMOylation signaling networks in a site-specific RT manner."; RL Nat. Struct. Mol. Biol. 21:927-936(2014). RN [33] RP INTERACTION WITH WRAP53. RX PubMed=26734725; DOI=10.1080/19491034.2015.1106675; RA Rassoolzadeh H., Coucoravas C., Farnebo M.; RT "The proximity ligation assay reveals that at DNA double-strand breaks RT WRAP53beta associates with gammaH2AX and controls interactions between RNF8 RT and MDC1."; RL Nucleus 6:417-424(2015). RN [34] RP SUMOYLATION [LARGE SCALE ANALYSIS] AT LYS-128 AND LYS-135, AND RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=28112733; DOI=10.1038/nsmb.3366; RA Hendriks I.A., Lyon D., Young C., Jensen L.J., Vertegaal A.C., RA Nielsen M.L.; RT "Site-specific mapping of the human SUMO proteome reveals co-modification RT with phosphorylation."; RL Nat. Struct. Mol. Biol. 24:325-336(2017). RN [35] RP INTERACTION WITH WRAP53. RX PubMed=27715493; DOI=10.1080/15476286.2016.1243647; RA Coucoravas C., Dhanjal S., Henriksson S., Boehm S., Farnebo M.; RT "Phosphorylation of the Cajal body protein WRAP53beta by ATM promotes its RT involvement in the DNA damage response."; RL RNA Biol. 14:804-813(2017). RN [36] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 134-143, AND PHOSPHORYLATION AT RP SER-140. RX PubMed=22154951; DOI=10.1016/j.jsb.2011.11.022; RA Shao Z., Li F., Sy S.M., Yan W., Zhang Z., Gong D., Wen B., Huen M.S., RA Gong Q., Wu J., Shi Y.; RT "Specific recognition of phosphorylated tail of H2AX by the tandem BRCT RT domains of MCPH1 revealed by complex structure."; RL J. Struct. Biol. 177:459-468(2012). CC -!- FUNCTION: Variant histone H2A which replaces conventional H2A in a CC subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, CC limiting DNA accessibility to the cellular machineries which require CC DNA as a template. Histones thereby play a central role in CC transcription regulation, DNA repair, DNA replication and chromosomal CC stability. DNA accessibility is regulated via a complex set of post- CC translational modifications of histones, also called histone code, and CC nucleosome remodeling. Required for checkpoint-mediated arrest of cell CC cycle progression in response to low doses of ionizing radiation and CC for efficient repair of DNA double strand breaks (DSBs) specifically CC when modified by C-terminal phosphorylation. CC {ECO:0000269|PubMed:10959836, ECO:0000269|PubMed:12419185, CC ECO:0000269|PubMed:12607005, ECO:0000269|PubMed:15201865}. CC -!- SUBUNIT: The nucleosome is a histone octamer containing two molecules CC each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and CC two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA CC (Probable). Interacts with numerous proteins required for DNA damage CC signaling and repair when phosphorylated on Ser-140 (PubMed:12419185, CC PubMed:12607005, PubMed:15201865). These include MDC1, TP53BP1, BRCA1 CC and the MRN complex, composed of MRE11, RAD50, and NBN CC (PubMed:12419185, PubMed:12607005, PubMed:15201865). Interaction with CC the MRN complex is mediated at least in part by NBN (PubMed:12419185). CC Also interacts with DHX9/NDHII when phosphorylated on Ser-140 and MCPH1 CC when phosphorylated at Ser-140 or Tyr-143 (PubMed:15613478). Interacts CC with ARRB2; the interaction is detected in the nucleus upon OR1D2 CC stimulation (PubMed:16820410). Interacts with WRAP53/TCAB1 CC (PubMed:26734725, PubMed:27715493). {ECO:0000269|PubMed:12419185, CC ECO:0000269|PubMed:12607005, ECO:0000269|PubMed:15201865, CC ECO:0000269|PubMed:15613478, ECO:0000269|PubMed:16820410, CC ECO:0000269|PubMed:26734725, ECO:0000269|PubMed:27715493, ECO:0000305}. CC -!- SUBUNIT: (Microbial infection) Interacts with Epstein-Barr virus CC protein EBNA6. {ECO:0000269|PubMed:24429368}. CC -!- INTERACTION: CC P16104; P38398: BRCA1; NbExp=4; IntAct=EBI-494830, EBI-349905; CC P16104; P58876: H2BC5; NbExp=2; IntAct=EBI-494830, EBI-4409942; CC P16104; Q16695: H3-4; NbExp=12; IntAct=EBI-494830, EBI-358900; CC P16104; P62805: H4C9; NbExp=5; IntAct=EBI-494830, EBI-302023; CC P16104; P02545: LMNA; NbExp=3; IntAct=EBI-494830, EBI-351935; CC P16104; P45983: MAPK8; NbExp=3; IntAct=EBI-494830, EBI-286483; CC P16104; Q14676: MDC1; NbExp=21; IntAct=EBI-494830, EBI-495644; CC P16104; P49959: MRE11; NbExp=7; IntAct=EBI-494830, EBI-396513; CC P16104; O60934: NBN; NbExp=14; IntAct=EBI-494830, EBI-494844; CC P16104; Q6ZW49-1: PAXIP1; NbExp=7; IntAct=EBI-494830, EBI-7521368; CC P16104; O15297: PPM1D; NbExp=3; IntAct=EBI-494830, EBI-1551512; CC P16104; P51532: SMARCA4; NbExp=9; IntAct=EBI-494830, EBI-302489; CC P16104; Q15554: TERF2; NbExp=4; IntAct=EBI-494830, EBI-706637; CC P16104; Q12888: TP53BP1; NbExp=6; IntAct=EBI-494830, EBI-396540; CC P16104; Q99986: VRK1; NbExp=3; IntAct=EBI-494830, EBI-1769146; CC P16104; PRO_0000022031 [Q9Z0X1]: Aifm1; Xeno; NbExp=2; IntAct=EBI-494830, EBI-5326677; CC P16104; P46933-1: Apbb1; Xeno; NbExp=2; IntAct=EBI-494830, EBI-15759525; CC P16104; Q6P4T3: Eya3; Xeno; NbExp=2; IntAct=EBI-494830, EBI-15759383; CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:12419185, CC ECO:0000269|PubMed:12660252, ECO:0000269|PubMed:12697768, CC ECO:0000269|PubMed:15613478, ECO:0000269|PubMed:24429368}. Chromosome CC {ECO:0000269|PubMed:10959836, ECO:0000269|PubMed:11673449, CC ECO:0000269|PubMed:12607005, ECO:0000269|PubMed:12660252, CC ECO:0000269|PubMed:15059890, ECO:0000269|PubMed:15201865, CC ECO:0000269|PubMed:15613478}. CC -!- DEVELOPMENTAL STAGE: Synthesized in G1 as well as in S-phase. CC -!- DOMAIN: The [ST]-Q motif constitutes a recognition sequence for kinases CC from the PI3/PI4-kinase family. CC -!- PTM: Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in CC response to DNA double strand breaks (DSBs) generated by exogenous CC genotoxic agents and by stalled replication forks, and may also occur CC during meiotic recombination events and immunoglobulin class switching CC in lymphocytes. Phosphorylation can extend up to several thousand CC nucleosomes from the actual site of the DSB and may mark the CC surrounding chromatin for recruitment of proteins required for DNA CC damage signaling and repair. Widespread phosphorylation may also serve CC to amplify the damage signal or aid repair of persistent lesions. CC Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing CC radiation is mediated by both ATM and PRKDC while defects in DNA CC replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to CC activation of ATR and PRKDC. Dephosphorylation of Ser-140 by PP2A is CC required for DNA DSB repair. In meiosis, Ser-140 phosphorylation CC (H2AX139ph) may occur at synaptonemal complexes during leptotene as an CC ATM-dependent response to the formation of programmed DSBs by SPO11. CC Ser-140 phosphorylation (H2AX139ph) may subsequently occurs at CC unsynapsed regions of both autosomes and the XY bivalent during CC zygotene, downstream of ATR and BRCA1 activation. Ser-140 CC phosphorylation (H2AX139ph) may also be required for transcriptional CC repression of unsynapsed chromatin and meiotic sex chromosome CC inactivation (MSCI), whereby the X and Y chromosomes condense in CC pachytene to form the heterochromatic XY-body. During immunoglobulin CC class switch recombination in lymphocytes, Ser-140 phosphorylation CC (H2AX139ph) may occur at sites of DNA-recombination subsequent to CC activation of the activation-induced cytidine deaminase AICDA. CC Phosphorylation at Tyr-143 (H2AXY142ph) by BAZ1B/WSTF determines the CC relative recruitment of either DNA repair or pro-apoptotic factors. CC Phosphorylation at Tyr-143 (H2AXY142ph) favors the recruitment of CC APBB1/FE65 and pro-apoptosis factors such as MAPK8/JNK1, triggering CC apoptosis. In contrast, dephosphorylation of Tyr-143 by EYA proteins CC (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing CC DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph). CC {ECO:0000269|PubMed:10477747, ECO:0000269|PubMed:10734083, CC ECO:0000269|PubMed:10959836, ECO:0000269|PubMed:11673449, CC ECO:0000269|PubMed:12419185, ECO:0000269|PubMed:12607005, CC ECO:0000269|PubMed:12660252, ECO:0000269|PubMed:12697768, CC ECO:0000269|PubMed:14627815, ECO:0000269|PubMed:15059890, CC ECO:0000269|PubMed:15489221, ECO:0000269|PubMed:15613478, CC ECO:0000269|PubMed:19092802, ECO:0000269|PubMed:19234442, CC ECO:0000269|PubMed:22154951, ECO:0000269|PubMed:9488723}. CC -!- PTM: Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 CC complex gives a specific tag for epigenetic transcriptional repression CC (By similarity). Following DNA double-strand breaks (DSBs), it is CC ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 CC ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the CC recruitment of repair proteins to sites of DNA damage. Ubiquitination CC at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response CC to DNA damage is initiated by RNF168 that mediates monoubiquitination CC at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to CC monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains CC in vitro. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked CC ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events. CC {ECO:0000250, ECO:0000269|PubMed:18001824, ECO:0000269|PubMed:18001825, CC ECO:0000269|PubMed:19203578, ECO:0000269|PubMed:19203579, CC ECO:0000269|PubMed:22980979}. CC -!- PTM: Acetylation at Lys-37 increases in S and G2 phases. This CC modification has been proposed to play a role in DNA double-strand CC break repair (By similarity). {ECO:0000250}. CC -!- SIMILARITY: Belongs to the histone H2A family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=NIEHS-SNPs; CC URL="http://egp.gs.washington.edu/data/h2afx/"; CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and CC Haematology; CC URL="http://atlasgeneticsoncology.org/Genes/H2AFXID40783ch11q23.html"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X14850; CAA32968.1; -; mRNA. DR EMBL; CR457079; CAG33360.1; -; mRNA. DR EMBL; DQ015918; AAY22178.1; -; Genomic_DNA. DR EMBL; BC004915; AAH04915.1; -; mRNA. DR EMBL; BC011694; AAH11694.1; -; mRNA. DR EMBL; BC013416; AAH13416.1; -; mRNA. DR CCDS; CCDS8410.1; -. DR PIR; S07631; S07631. DR RefSeq; NP_002096.1; NM_002105.2. DR PDB; 1YDP; X-ray; 1.90 A; P=78-86. DR PDB; 2AZM; X-ray; 2.41 A; C/D=134-143. DR PDB; 2D31; X-ray; 3.20 A; C/F=78-86. DR PDB; 2DYP; X-ray; 2.50 A; C=78-86. DR PDB; 3SHV; X-ray; 2.10 A; C/D=134-143. DR PDB; 3SQD; X-ray; 2.15 A; C/D=134-143. DR PDB; 3SZM; X-ray; 2.63 A; I/J/K/L/M/N/O/P=134-143. DR PDB; 3U3Z; X-ray; 1.50 A; B=140-143. DR PDB; 6K1I; X-ray; 2.75 A; C/G=1-143. DR PDB; 6K1J; X-ray; 2.85 A; C/G=1-143. DR PDB; 6K1K; X-ray; 2.20 A; C/G=1-143. DR PDBsum; 1YDP; -. DR PDBsum; 2AZM; -. DR PDBsum; 2D31; -. DR PDBsum; 2DYP; -. DR PDBsum; 3SHV; -. DR PDBsum; 3SQD; -. DR PDBsum; 3SZM; -. DR PDBsum; 3U3Z; -. DR PDBsum; 6K1I; -. DR PDBsum; 6K1J; -. DR PDBsum; 6K1K; -. DR SMR; P16104; -. DR BioGRID; 109268; 450. DR CORUM; P16104; -. DR DIP; DIP-33604N; -. DR ELM; P16104; -. DR IntAct; P16104; 290. DR MINT; P16104; -. DR STRING; 9606.ENSP00000434024; -. DR iPTMnet; P16104; -. DR PhosphoSitePlus; P16104; -. DR SwissPalm; P16104; -. DR BioMuta; H2AFX; -. DR DMDM; 121992; -. DR EPD; P16104; -. DR jPOST; P16104; -. DR MassIVE; P16104; -. DR MaxQB; P16104; -. DR PaxDb; P16104; -. DR PeptideAtlas; P16104; -. DR PRIDE; P16104; -. DR ProteomicsDB; 53286; -. DR TopDownProteomics; P16104; -. DR Antibodypedia; 3220; 1513 antibodies. DR Ensembl; ENST00000375167; ENSP00000364310; ENSG00000188486. DR Ensembl; ENST00000530167; ENSP00000434024; ENSG00000188486. DR GeneID; 3014; -. DR KEGG; hsa:3014; -. DR UCSC; uc001pvg.4; human. DR CTD; 3014; -. DR DisGeNET; 3014; -. DR GeneCards; H2AX; -. DR HGNC; HGNC:4739; H2AX. DR HPA; ENSG00000188486; Tissue enriched (lymphoid). DR MIM; 601772; gene. DR neXtProt; NX_P16104; -. DR OpenTargets; ENSG00000188486; -. DR PharmGKB; PA29116; -. DR VEuPathDB; HostDB:ENSG00000188486.3; -. DR eggNOG; KOG1756; Eukaryota. DR GeneTree; ENSGT01020000230570; -. DR HOGENOM; CLU_062828_3_1_1; -. DR InParanoid; P16104; -. DR OMA; KANSGRD; -. DR OrthoDB; 1504122at2759; -. DR PhylomeDB; P16104; -. DR TreeFam; TF300137; -. DR PathwayCommons; P16104; -. DR Reactome; R-HSA-110328; Recognition and association of DNA glycosylase with site containing an affected pyrimidine. DR Reactome; R-HSA-110329; Cleavage of the damaged pyrimidine. DR Reactome; R-HSA-110330; Recognition and association of DNA glycosylase with site containing an affected purine. DR Reactome; R-HSA-110331; Cleavage of the damaged purine. DR Reactome; R-HSA-1221632; Meiotic synapsis. DR Reactome; R-HSA-171306; Packaging Of Telomere Ends. DR Reactome; R-HSA-1912408; Pre-NOTCH Transcription and Translation. DR Reactome; R-HSA-201722; Formation of the beta-catenin:TCF transactivating complex. DR Reactome; R-HSA-212300; PRC2 methylates histones and DNA. DR Reactome; R-HSA-2299718; Condensation of Prophase Chromosomes. DR Reactome; R-HSA-2559580; Oxidative Stress Induced Senescence. DR Reactome; R-HSA-2559582; Senescence-Associated Secretory Phenotype (SASP). DR Reactome; R-HSA-2559586; DNA Damage/Telomere Stress Induced Senescence. DR Reactome; R-HSA-3214858; RMTs methylate histone arginines. DR Reactome; R-HSA-427359; SIRT1 negatively regulates rRNA expression. DR Reactome; R-HSA-427389; ERCC6 (CSB) and EHMT2 (G9a) positively regulate rRNA expression. DR Reactome; R-HSA-427413; NoRC negatively regulates rRNA expression. DR Reactome; R-HSA-5250924; B-WICH complex positively regulates rRNA expression. DR Reactome; R-HSA-5334118; DNA methylation. DR Reactome; R-HSA-5578749; Transcriptional regulation by small RNAs. DR Reactome; R-HSA-5617472; Activation of anterior HOX genes in hindbrain development during early embryogenesis. DR Reactome; R-HSA-5625886; Activated PKN1 stimulates transcription of AR (androgen receptor) regulated genes KLK2 and KLK3. DR Reactome; R-HSA-5693565; Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks. DR Reactome; R-HSA-5693571; Nonhomologous End-Joining (NHEJ). DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends. DR Reactome; R-HSA-606279; Deposition of new CENPA-containing nucleosomes at the centromere. DR Reactome; R-HSA-69473; G2/M DNA damage checkpoint. DR Reactome; R-HSA-73728; RNA Polymerase I Promoter Opening. DR Reactome; R-HSA-73772; RNA Polymerase I Promoter Escape. DR Reactome; R-HSA-8936459; RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function. DR Reactome; R-HSA-8939236; RUNX1 regulates transcription of genes involved in differentiation of HSCs. DR Reactome; R-HSA-9018519; Estrogen-dependent gene expression. DR Reactome; R-HSA-912446; Meiotic recombination. DR Reactome; R-HSA-9616222; Transcriptional regulation of granulopoiesis. DR Reactome; R-HSA-9670095; Inhibition of DNA recombination at telomere. DR Reactome; R-HSA-977225; Amyloid fiber formation. DR SIGNOR; P16104; -. DR BioGRID-ORCS; 3014; 297 hits in 997 CRISPR screens. DR ChiTaRS; H2AFX; human. DR EvolutionaryTrace; P16104; -. DR GeneWiki; H2AFX; -. DR GenomeRNAi; 3014; -. DR Pharos; P16104; Tbio. DR PRO; PR:P16104; -. DR Proteomes; UP000005640; Chromosome 11. DR RNAct; P16104; protein. DR Bgee; ENSG00000188486; Expressed in ventricular zone and 238 other tissues. DR Genevisible; P16104; HS. DR GO; GO:0005813; C:centrosome; IDA:UniProtKB. DR GO; GO:0000794; C:condensed nuclear chromosome; IEA:Ensembl. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0001673; C:male germ cell nucleus; IEA:Ensembl. DR GO; GO:0016607; C:nuclear speck; IDA:HPA. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0000786; C:nucleosome; IEA:UniProtKB-KW. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0005657; C:replication fork; IEA:Ensembl. DR GO; GO:0090734; C:site of DNA damage; IMP:UniProtKB. DR GO; GO:0035861; C:site of double-strand break; IDA:MGI. DR GO; GO:0001741; C:XY body; IEA:Ensembl. DR GO; GO:0003684; F:damaged DNA binding; IEA:Ensembl. DR GO; GO:0003677; F:DNA binding; IBA:GO_Central. DR GO; GO:0019899; F:enzyme binding; IPI:UniProtKB. DR GO; GO:0042393; F:histone binding; IPI:UniProtKB. DR GO; GO:0046982; F:protein heterodimerization activity; IEA:InterPro. DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:BHF-UCL. DR GO; GO:0071480; P:cellular response to gamma radiation; IEA:Ensembl. DR GO; GO:0090398; P:cellular senescence; IEA:Ensembl. DR GO; GO:0021987; P:cerebral cortex development; IEA:Ensembl. DR GO; GO:0006342; P:chromatin silencing; IBA:GO_Central. DR GO; GO:0000077; P:DNA damage checkpoint; IDA:UniProtKB. DR GO; GO:0006302; P:double-strand break repair; TAS:Reactome. DR GO; GO:0000724; P:double-strand break repair via homologous recombination; IEA:Ensembl. DR GO; GO:0006303; P:double-strand break repair via nonhomologous end joining; TAS:Reactome. DR GO; GO:0051321; P:meiotic cell cycle; IEA:UniProtKB-KW. DR GO; GO:0006334; P:nucleosome assembly; NAS:UniProtKB. DR GO; GO:0045739; P:positive regulation of DNA repair; NAS:UniProtKB. DR GO; GO:0010212; P:response to ionizing radiation; NAS:UniProtKB. DR GO; GO:0007283; P:spermatogenesis; IEA:Ensembl. DR GO; GO:0016032; P:viral process; IEA:UniProtKB-KW. DR CDD; cd00074; H2A; 1. DR Gene3D; 1.10.20.10; -; 1. DR IDEAL; IID00027; -. DR InterPro; IPR009072; Histone-fold. DR InterPro; IPR002119; Histone_H2A. DR InterPro; IPR007125; Histone_H2A/H2B/H3. DR InterPro; IPR032454; Histone_H2A_C. DR InterPro; IPR032458; Histone_H2A_CS. DR Pfam; PF00125; Histone; 1. DR Pfam; PF16211; Histone_H2A_C; 1. DR PRINTS; PR00620; HISTONEH2A. DR SMART; SM00414; H2A; 1. DR SUPFAM; SSF47113; SSF47113; 1. DR PROSITE; PS00046; HISTONE_H2A; 1. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cell cycle; Chromosome; DNA damage; KW DNA recombination; DNA repair; DNA-binding; Host-virus interaction; KW Isopeptide bond; Meiosis; Nucleosome core; Nucleus; Phosphoprotein; KW Reference proteome; Ubl conjugation. FT INIT_MET 1 FT /note="Removed" FT /evidence="ECO:0000250|UniProtKB:P27661" FT CHAIN 2..143 FT /note="Histone H2AX" FT /id="PRO_0000055242" FT MOTIF 140..141 FT /note="[ST]-Q motif" FT MOD_RES 2 FT /note="N-acetylserine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 2 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 6 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 10 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 10 FT /note="N6-lactoyllysine; alternate" FT /evidence="ECO:0000250|UniProtKB:P0C0S5" FT MOD_RES 37 FT /note="N6-acetyllysine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 122 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P27661" FT MOD_RES 140 FT /note="Phosphoserine; by ATM, ATR and PRKDC" FT /evidence="ECO:0000269|PubMed:10477747, FT ECO:0000269|PubMed:10734083, ECO:0000269|PubMed:10959836, FT ECO:0000269|PubMed:11673449, ECO:0000269|PubMed:12419185, FT ECO:0000269|PubMed:12607005, ECO:0000269|PubMed:12660252, FT ECO:0000269|PubMed:12697768, ECO:0000269|PubMed:14627815, FT ECO:0000269|PubMed:15059890, ECO:0000269|PubMed:15489221, FT ECO:0000269|PubMed:15613478, ECO:0000269|PubMed:22154951, FT ECO:0000269|PubMed:9488723, ECO:0007744|PubMed:17525332, FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692" FT MOD_RES 143 FT /note="Phosphotyrosine; by WSTF" FT /evidence="ECO:0000269|PubMed:19092802, FT ECO:0000269|PubMed:19234442" FT CROSSLNK 14 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:22980979" FT CROSSLNK 16 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:22980979" FT CROSSLNK 120 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000250|UniProtKB:P27661" FT CROSSLNK 128 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:28112733" FT CROSSLNK 135 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in SUMO2)" FT /evidence="ECO:0007744|PubMed:25218447, FT ECO:0007744|PubMed:28112733" FT MUTAGEN 141 FT /note="Q->N: Reduced phosphorylation of S-140 in response FT to DNA damage." FT /evidence="ECO:0000269|PubMed:9488723" FT MUTAGEN 143 FT /note="Y->F: Displays a reduced apoptotic response. S-140 FT phosphorylation is reduced." FT /evidence="ECO:0000269|PubMed:19092802, FT ECO:0000269|PubMed:19234442" FT CONFLICT 78 FT /note="R -> L (in Ref. 2; CAG33360)" FT /evidence="ECO:0000305" FT HELIX 18..22 FT /evidence="ECO:0007744|PDB:6K1K" FT HELIX 28..37 FT /evidence="ECO:0007744|PDB:6K1K" FT STRAND 42..44 FT /evidence="ECO:0007744|PDB:6K1K" FT HELIX 47..73 FT /evidence="ECO:0007744|PDB:6K1K" FT STRAND 77..79 FT /evidence="ECO:0007744|PDB:6K1K" FT HELIX 81..90 FT /evidence="ECO:0007744|PDB:6K1K" FT HELIX 92..97 FT /evidence="ECO:0007744|PDB:6K1K" FT TURN 98..100 FT /evidence="ECO:0007744|PDB:6K1K" FT STRAND 101..103 FT /evidence="ECO:0007744|PDB:6K1I" FT HELIX 114..116 FT /evidence="ECO:0007744|PDB:6K1K" SQ SEQUENCE 143 AA; 15145 MW; D4683775C2E6C3A9 CRC64; MSGRGKTGGK ARAKAKSRSS RAGLQFPVGR VHRLLRKGHY AERVGAGAPV YLAAVLEYLT AEILELAGNA ARDNKKTRII PRHLQLAIRN DEELNKLLGG VTIAQGGVLP NIQAVLLPKK TSATVGPKAP SGGKKATQAS QEY //