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Gene Review

H2AFX  -  H2A histone family, member X

Homo sapiens

Synonyms: H2A.X, H2A/X, H2AX, H2a/x, Histone H2A.X, ...
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Disease relevance of H2AFX


High impact information on H2AFX

  • Although it is known that MSCI and MSUC are both dependent on histone H2A.X phosphorylation mediated by the kinase ATR, and cause repressive H3 Lys9 dimethylation, the mechanisms underlying silencing are largely unidentified [6].
  • MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks [7].
  • Histone variant H2AX phosphorylation in response to DNA damage is the major signal for recruitment of DNA-damage-response proteins to regions of damaged chromatin [7].
  • Loss of H2AX causes radiosensitivity, genome instability, and DNA double-strand-break repair defects, yet the mechanisms underlying these phenotypes remain obscure [7].
  • Moreover, H2AX haploinsufficiency caused genomic instability in normal cells and, on a p53-deficient background, early onset of various tumors including more mature B lymphomas [5].

Chemical compound and disease context of H2AFX


Biological context of H2AFX

  • Furthermore, this interaction is phosphorylation dependent as peptides containing the phosphorylated site on H2AX bind MDC1 in a phosphorylation-dependent manner [9].
  • Here we identify a novel BRCA1 carboxy-terminal (BRCT) and forkhead-associated (FHA) domain-containing protein, MDC1 (mediator of DNA damage checkpoint protein 1), which works with H2AX to promote recruitment of repair proteins to the sites of DNA breaks and which, in addition, controls damage-induced cell-cycle arrest checkpoints [9].
  • It has recently been shown that the histone H2A variant H2AX specifically controls the recruitment of DNA repair proteins to the sites of DNA damage [9].
  • Our findings suggest that, in addition to its role in the recognition and repair of double strand breaks, H2AX also participates in the surveillance of DNA replication [10].
  • Thereby, the NDH II DEXH domain alone, i.e. its catalytic core, was able to support binding to gamma-H2AX [11].

Anatomical context of H2AFX


Associations of H2AFX with chemical compounds

  • Mammalian ATR and ATM checkpoint kinases modulate chromatin structures near DNA breaks by phosphorylating a serine residue in the carboxy-terminal tail SQE motif of histone H2AX [16].
  • Here we report that inhibition of DNA replication by hydroxyurea or ultraviolet irradiation also induces phosphorylation and foci formation of H2AX [10].
  • Congruently, after actinomycin D treatment, NDH II accumulated in RNA-containing nuclear bodies that predominantly co-localized with gamma-H2AX foci [11].
  • Here we show that gamma-H2AX foci were also formed when cells were incubated with 0.5 microg/ml DNA intercalating agent actinomycin D [11].
  • Analysis of the radiation-induced H2AX phosphorylation revealed that BIBX, as well as the PI3K inhibitor LY294002, leads to a marked reduction of P-H2AX in K-RAS(mt)-A549 and MDA-MB-231 cells, but not in K-RAS(wt)-FaDu and HH4ded cells [17].

Physical interactions of H2AFX

  • With this procedure we found that both HMG1 and HMG2 interact with H2A X H2B and also with (H3 X H4)2 [18].

Enzymatic interactions of H2AFX

  • Rather, double mutant BLM protein induced the formation of DNA damage-induced foci (DDI) that contained BRCA1 protein and phosphorylated histone H2AX [19].
  • Like many proteins involved in the DNA damage response, 53BP1 becomes hyperphosphorylated after radiation and colocalizes with phosphorylated H2AX in megabase regions surrounding the sites of DNA strand breaks [20].

Co-localisations of H2AFX

  • MDC1 forms foci that co-localize extensively with gamma-H2AX foci within minutes after exposure to ionizing radiation [9].
  • At this time, a significant fraction of the gamma-H2AX nuclear foci co-localized with the foci of RAD50 protein that did not co-localize with replication sites [21].

Regulatory relationships of H2AFX

  • Additionally, we show that inactivation of both DNA-PK and ATM is required to ablate IR-induced H2AX phosphorylation in chicken cells [22].
  • Taken together, these results suggest that histone gamma-H2AX promotes binding of NDH II to transcriptionally stalled sites on chromosomal DNA [11].
  • This study provides evidence for the importance of p21(CDKN1A) for the repair of replication-mediated DNA double-strand breaks (DSBs) induced by topoisomerase I. We report that defects of p21(CDKN1A) and p53 enhance camptothecin-induced histone H2AX phosphorylation (gammaH2AX), a marker for DNA DSBs [23].
  • In both cell lines, the highest degree of H2AX phosphorylation induced by UV was seen in S-phase cells, particularly during early portion of S [24].
  • We further show that MDC1/NFBD1-gammaH2AX complex formation regulates H2AX phosphorylation and is required for normal radioresistance and efficient accumulation of DNA-damage-response proteins on damaged chromatin [7].
  • TIP60 regulates the ubiquitination of H2AX via the ubiquitin-conjugating enzyme UBC13, which is induced by DNA damage [25].
  • The treatment of cytosine-beta-D-arabinofuranoside strikingly enhances the NER-dependent H2AX phosphorylation and induces the accumulation of replication protein A (RPA) and ATR-interacting protein (ATRIP) at locally UV-damaged subnuclear regions [26].

Other interactions of H2AFX


Analytical, diagnostic and therapeutic context of H2AFX


  1. Melanoma cells express elevated levels of phosphorylated histone H2AX foci. Warters, R.L., Adamson, P.J., Pond, C.D., Leachman, S.A. J. Invest. Dermatol. (2005) [Pubmed]
  2. The Haemophilus ducreyi cytolethal distending toxin activates sensors of DNA damage and repair complexes in proliferating and non-proliferating cells. Li, L., Sharipo, A., Chaves-Olarte, E., Masucci, M.G., Levitsky, V., Thelestam, M., Frisan, T. Cell. Microbiol. (2002) [Pubmed]
  3. Hedamycin, a DNA alkylator, induces (gamma)H2AX and chromosome aberrations: involvement of phosphatidylinositol 3-kinase-related kinases and DNA replication fork movement. Tu, L.C., Matsui, S.I., Beerman, T.A. Mol. Cancer Ther. (2005) [Pubmed]
  4. Non-homologous end joining, but not homologous recombination, enables survival for cells exposed to a histone deacetylase inhibitor. Yaneva, M., Li, H., Marple, T., Hasty, P. Nucleic Acids Res. (2005) [Pubmed]
  5. Histone H2AX: a dosage-dependent suppressor of oncogenic translocations and tumors. Bassing, C.H., Suh, H., Ferguson, D.O., Chua, K.F., Manis, J., Eckersdorff, M., Gleason, M., Bronson, R., Lee, C., Alt, F.W. Cell (2003) [Pubmed]
  6. Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation. van der Heijden, G.W., Derijck, A.A., Pósfai, E., Giele, M., Pelczar, P., Ramos, L., Wansink, D.G., van der Vlag, J., Peters, A.H., de Boer, P. Nat. Genet. (2007) [Pubmed]
  7. MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Stucki, M., Clapperton, J.A., Mohammad, D., Yaffe, M.B., Smerdon, S.J., Jackson, S.P. Cell (2005) [Pubmed]
  8. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Liu, Y., Tseng, M., Perdreau, S.A., Rossi, F., Antonescu, C., Besmer, P., Fletcher, J.A., Duensing, S., Duensing, A. Cancer Res. (2007) [Pubmed]
  9. MDC1 is a mediator of the mammalian DNA damage checkpoint. Stewart, G.S., Wang, B., Bignell, C.R., Taylor, A.M., Elledge, S.J. Nature (2003) [Pubmed]
  10. Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. Ward, I.M., Chen, J. J. Biol. Chem. (2001) [Pubmed]
  11. Actinomycin D induces histone gamma-H2AX foci and complex formation of gamma-H2AX with Ku70 and nuclear DNA helicase II. Mischo, H.E., Hemmerich, P., Grosse, F., Zhang, S. J. Biol. Chem. (2005) [Pubmed]
  12. Phosphorylation of histone H2AX and activation of Mre11, Rad50, and Nbs1 in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. Furuta, T., Takemura, H., Liao, Z.Y., Aune, G.J., Redon, C., Sedelnikova, O.A., Pilch, D.R., Rogakou, E.P., Celeste, A., Chen, H.T., Nussenzweig, A., Aladjem, M.I., Bonner, W.M., Pommier, Y. J. Biol. Chem. (2003) [Pubmed]
  13. Relationship between DNA double-strand break rejoining and cell survival after exposure to ionizing radiation in human fibroblast strains with differing ATM/p53 status: Implications for evaluation of clinical radiosensitivity. Mirzayans, R., Severin, D., Murray, D. Int. J. Radiat. Oncol. Biol. Phys. (2006) [Pubmed]
  14. Chromosomal localization of the human histone H2A.X gene to 11q23.2-q23.3 by fluorescence in situ hybridization. Ivanova, V.S., Zimonjic, D., Popescu, N., Bonner, W.M. Hum. Genet. (1994) [Pubmed]
  15. ATM activation and histone H2AX phosphorylation as indicators of DNA damage by DNA topoisomerase I inhibitor topotecan and during apoptosis. Tanaka, T., Kurose, A., Huang, X., Dai, W., Darzynkiewicz, Z. Cell Prolif. (2006) [Pubmed]
  16. Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. Nakamura, T.M., Du, L.L., Redon, C., Russell, P. Mol. Cell. Biol. (2004) [Pubmed]
  17. Blockage of epidermal growth factor receptor-phosphatidylinositol 3-kinase-AKT signaling increases radiosensitivity of K-RAS mutated human tumor cells in vitro by affecting DNA repair. Toulany, M., Kasten-Pisula, U., Brammer, I., Wang, S., Chen, J., Dittmann, K., Baumann, M., Dikomey, E., Rodemann, H.P. Clin. Cancer Res. (2006) [Pubmed]
  18. Identification of the core-histone-binding domains of HMG1 and HMG2. Bernués, J., Espel, E., Querol, E. Biochim. Biophys. Acta (1986) [Pubmed]
  19. Intra-nuclear trafficking of the BLM helicase to DNA damage-induced foci is regulated by SUMO modification. Eladad, S., Ye, T.Z., Hu, P., Leversha, M., Beresten, S., Matunis, M.J., Ellis, N.A. Hum. Mol. Genet. (2005) [Pubmed]
  20. Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX. Ward, I.M., Minn, K., Jorda, K.G., Chen, J. J. Biol. Chem. (2003) [Pubmed]
  21. Dephosphorylation of histone gamma-H2AX during repair of DNA double-strand breaks in mammalian cells and its inhibition by calyculin A. Nazarov, I.B., Smirnova, A.N., Krutilina, R.I., Svetlova, M.P., Solovjeva, L.V., Nikiforov, A.A., Oei, S.L., Zalenskaya, I.A., Yau, P.M., Bradbury, E.M., Tomilin, N.V. Radiat. Res. (2003) [Pubmed]
  22. ATM and DNA-PK function redundantly to phosphorylate H2AX after exposure to ionizing radiation. Stiff, T., O'Driscoll, M., Rief, N., Iwabuchi, K., Löbrich, M., Jeggo, P.A. Cancer Res. (2004) [Pubmed]
  23. p21CDKN1A allows the repair of replication-mediated DNA double-strand breaks induced by topoisomerase I and is inactivated by the checkpoint kinase inhibitor 7-hydroxystaurosporine. Furuta, T., Hayward, R.L., Meng, L.H., Takemura, H., Aune, G.J., Bonner, W.M., Aladjem, M.I., Kohn, K.W., Pommier, Y. Oncogene (2006) [Pubmed]
  24. Histone H2AX phosphorylation after cell irradiation with UV-B: relationship to cell cycle phase and induction of apoptosis. Halicka, H.D., Huang, X., Traganos, F., King, M.A., Dai, W., Darzynkiewicz, Z. Cell Cycle (2005) [Pubmed]
  25. DNA damage-dependent acetylation and ubiquitination of H2AX enhances chromatin dynamics. Ikura, T., Tashiro, S., Kakino, A., Shima, H., Jacob, N., Amunugama, R., Yoder, K., Izumi, S., Kuraoka, I., Tanaka, K., Kimura, H., Ikura, M., Nishikubo, S., Ito, T., Muto, A., Miyagawa, K., Takeda, S., Fishel, R., Igarashi, K., Kamiya, K. Mol. Cell. Biol. (2007) [Pubmed]
  26. Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells. Matsumoto, M., Yaginuma, K., Igarashi, A., Imura, M., Hasegawa, M., Iwabuchi, K., Date, T., Mori, T., Ishizaki, K., Yamashita, K., Inobe, M., Matsunaga, T. J. Cell. Sci. (2007) [Pubmed]
  27. Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX-dependent chromatin retention. Lukas, C., Melander, F., Stucki, M., Falck, J., Bekker-Jensen, S., Goldberg, M., Lerenthal, Y., Jackson, S.P., Bartek, J., Lukas, J. EMBO J. (2004) [Pubmed]
  28. A subset of ATM- and ATR-dependent phosphorylation events requires the BRCA1 protein. Foray, N., Marot, D., Gabriel, A., Randrianarison, V., Carr, A.M., Perricaudet, M., Ashworth, A., Jeggo, P. EMBO J. (2003) [Pubmed]
  29. Doxorubicin activates ATM-dependent phosphorylation of multiple downstream targets in part through the generation of reactive oxygen species. Kurz, E.U., Douglas, P., Lees-Miller, S.P. J. Biol. Chem. (2004) [Pubmed]
  30. Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Brew, C.T., Aronchik, I., Hsu, J.C., Sheen, J.H., Dickson, R.B., Bjeldanes, L.F., Firestone, G.L. Int. J. Cancer (2006) [Pubmed]
  31. Complex H2AX phosphorylation patterns by multiple kinases including ATM and DNA-PK in human cells exposed to ionizing radiation and treated with kinase inhibitors. Wang, H., Wang, M., Wang, H., Böcker, W., Iliakis, G. J. Cell. Physiol. (2005) [Pubmed]
  32. CYP1A1 activation of aminoflavone leads to DNA damage in human tumor cell lines. Pobst, L.J., Ames, M.M. Cancer Chemother. Pharmacol. (2006) [Pubmed]
  33. H2A.X. a histone isoprotein with a conserved C-terminal sequence, is encoded by a novel mRNA with both DNA replication type and polyA 3' processing signals. Mannironi, C., Bonner, W.M., Hatch, C.L. Nucleic Acids Res. (1989) [Pubmed]
  34. Novel genotoxicity assays identify norethindrone to activate p53 and phosphorylate H2AX. Gallmeier, E., Winter, J.M., Cunningham, S.C., Kahn, S.R., Kern, S.E. Carcinogenesis (2005) [Pubmed]
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