• 1
    Moore, J. D. and J. E. Krebs (2004) Histone modifications and DNA double-strand break repair. Biochem. Cell Biol. 82, 446452.
  • 2
    Moore, J. D., O. Yazgan, Y. Ataian and J. E. Krebs (2007) Diverse pathways for histone 2A modifications in DNA damage response pathways in yeast. Genetics 176, 1525.
  • 3
    Lowndes, N. F. and G. W.-L. Toh (2005) DNA repair: The importance of phosphorylating histone H2AX. Curr. Biol. 15, R99R102.
  • 4
    Pinto, D. M. and A. Flaus (2010) Structure and function of histone H2AX. Subcell. Biochem. 50, 5578.
  • 5
    Kotova, E., N. Lodhi, M. Jarnik, A. D. Pinnola, Y. Ji and A. V. Tulin (2011) Drosophila histone H2A variant (H2Av) controls poly(ADP-ribose) polymerase 1 (PARP1) activation in chromatin. Proc. Natl Acad. Sci. USA 108, 62056210.
  • 6
    Halicka, H. D., X. Huang, F. Traganos, M. A. King, W. Dai and Z. Darzynkiewicz (2005) Histone H2AX phosphorylation after cell irradiation with UV-B: Relationship to cell cycle phase and induction of apoptosis. Cell Cycle 4, 339345.
  • 7
    Staszewski, O., T. Nikolova and B. Kaina (2008) Kinetics of gamma-H2AX focus formation upon treatment of cells with UV light and alkylating agents. Environ. Mol. Mutagen. 49, 734740.
  • 8
    Banath, J. P. and P. L. Olive (2003) Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks. Cancer Res. 63, 43474350.
  • 9
    Olive, P. L. and J. P. Banath (2009) Kinetics of H2AX phosphorylation after exposure to cisplatin. Cytometry B. Clin. Cytom. 76, 7990.
  • 10
    Lee, J. H., M. L. Choy, L. Ngo, S. S. Foster and P. A. Marks (2010) Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proc. Natl Acad. Sci. USA 107, 1463914644.
  • 11
    Namdar, M., G. Perez, L. Ngo and P. A. Marks (2010) Selective inhibition of histone deacetylase 6 (HDAC6) induces DNA damage and sensitizes transformed cells to anticancer agents. Proc. Natl Acad. Sci. USA 107, 2000320008.
  • 12
    Yin, B. and C. H. Bassing (2008) The sticky business of histone H2AX in V(D)J recombination, maintenance of genomic stability, and suppression of lymphoma. Immunol. Res. 42, 2940.
  • 13
    Fernandez-Capetillo, O., S. K. Mahadevaiah, A. Celeste, P. J. Romanienko, R. D. Camerini-Otero, W. M. Bonner, K. Manova, P. Burgoyne and A. Nussenzweig (2003) H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev. Cell 4, 497508.
  • 14
    Wossidlo, M., J. Arand, V. Sebastiano, K. Lepikhov, M. Boiani, R. Reinhardt, H. Schöler and J. Walter (2010) Dynamic link of DNA demethylation, DNA strand breaks and repair in mouse zygotes. EMBO J. 29, 18771888.
  • 15
    Shin, I. J., Y. T. Ahn, Y. Kim, J. M. Kim and W. G. An (2011) Actin disruption agents induce phosphorylation of histone H2AX in human breast adenocarcinoma MCF-7 cells. Oncol. Rep. 25, 13131319.
  • 16
    Fernando, R. N., B. Eleuteri, S. Abdelhady, A. Nussenzweig, M. Andäng and P. Ernfors (2011) Cell cycle restriction by histone H2AX limits proliferation of adult neural stem cells. Proc. Natl Acad. Sci. USA 108, 58375842.
  • 17
    de Feraudy, S., I. Revet, V. Bezrookove, L. Feeney and J. E. Cleaver (2010) A minority of foci or pan-nuclear apoptotic staining of gH2AX in the S phase after UV damage contain DNA double strand breaks. Proc. Natl Acad. Sci. USA 107, 68706875.
  • 18
    Revet, I., L. Feeney, S. Bruguera, W. Wilson, T. K. Dong, D. H. Oh, D. Dankort and J. E. Cleaver (2011) The functional relevance of gH2Ax in the response to DNA damaging agents. Proc. Natl Acad. Sci. USA 108, 86638667.
  • 19
    Matsuoka, S., B. A. Ballif, A. Smogorzewska, E. R. McDonald, K. E. Hurov, J. Luo, C. E. Bakalarski, Z. Zhao, N. Solimini, Y. Lerenthal, Y. Shiloh, S. P. Gygi and S. J. Elledge (2007) ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 316, 11601166.
  • 20
    Jazayeri, A., A. Balestrini, E. Garner, J. E. Haber and V. Costanzo (2008) Mre11-Rad50-Nbs1-dependent processing of DNA breaks generates oligonucleotides that stimulate ATM activity. EMBO J. 27, 19531962.
  • 21
    Guo, Z., S. Kozlov, M. F. Lavin, M. D. Person and T. T. Paull (2010) ATM activation by oxidative stress. Science 330, 517521.
  • 22
    Celeste, A., S. Petersen, P. J. Romanienko, O. Fernandez-Capetillo, H. T. Chen, O. A. Sedelnikova, B. Reina-San-Martin, V. Coppola, E. Meffre, M. J. Difilippantonio, C. Redon, D. R. Pilch, A. Olaru, M. Eckhaus, R. D. Camerini-Otero, L. Tessarollo, F. Livak, K. Manova, W. M. Bonner, M. C. Nussenzweig and A. Nussenzweig (2002) Genomic instability in mice lacking histone H2AX. Science 296, 922927.
  • 23
    Cortez, D., S. Guntuku, J. Qin and S. J. Elledge (2001) ATR and ATRIP: Partners in checkpoint signaling. Science 294, 17131716.
  • 24
    Zou, L. and S. J. Elledge (2003) Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science 300, 15421548.
  • 25
    Hurley, P. J. and F. Bunz (2007) ATM and ATR components of an integrated circuit. Cell Cycle 6, 414417.
  • 26
    Celeste, A., O. Fernandez-Capetillo, M. J. Kruhlak, D. R. Pilch, D. W. Staudt, A. Lee, R. F. Bonner, W. M. Bonner and A. Nussenzweig (2003) Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat. Cell Biol. 5, 675679.
  • 27
    Cook, P. J., B. G. Ju, F. Telese, X. Wang, C. K. Glass and M. G. Rosenfeld (2009) Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591596.
  • 28
    Rothkamm, K. and M. Lobrich (2003) Evidence for a lack of DNA double strand break repair in human cells exposed to very low X-ray doses. Proc. Natl Acad. Sci. USA 100, 50575062.
  • 29
    Limoli, C. L., E. Giedzinski, W. M. Bonner and J. E. Cleaver (2002) UV-induced replication arrest in the xeroderma pigmentosum variant leads to double strand breaks, g-H2Ax formation, and Mre11 relocalization. Proc. Natl Acad. Sci. USA 99, 233238.
  • 30
    Paull, T. T., E. P. Rogakou, V. Yamazaki, C. U. Kirchgessner, M. Gellert and W. M. Bonner (2000) A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10, 886895.
  • 31
    Lu, C., F. Zhu, Y. Y. Cho, F. Tang, T. Zykova, W. Y. Ma, A. M. Bode and Z. Dong (2006) Cell apoptosis: Requirement of H2AX in DNA ladder formation, but not for the activation of caspase-3. Mol. Cell 23, 121132.
  • 32
    Rogakou, E. P., W. Nieves-Neira, C. Boon, Y. Pommier and W. M. Bonner (2000) Initiation of DNA fragmentation during apoptosis induces phosphorylation of H2AX histone at serine 139. J. Biol. Chem. 275, 93909395.
  • 33
    Cleaver, J. E. (1989) Caffeine toxicity is inversely related to DNA repair in simian virus-40 transformed xeroderma pigmentosum cells irradiated with ultraviolet light. Teratog. Carcinog. Mutagen. 9, 147155.
  • 34
    Despras, E., F. Daboussi, O. Hyrien, K. Marheineke and P. L. Kannouche (2010) ATR/Chk1 pathway is essential for resumption of DNA synthesis and cell survival in UV-irradiated XP variant cells. Hum. Mol. Genet. 19, 16901701.
  • 35
    Heffernan, T. P., M. Kawasumi, A. Blasina, K. Anderes, A. Conney and P. Nghiem (2009) ATR-Chk1 pathway inhibition promotes apoptosis after UV treatment in primary human keratinocytes: Potential basis for the UV protective effects of caffeine. J. Invest. Dermatol. 129, 18051815.
  • 36
    Sarkaria, J. N., E. C. Busby, R. S. Tibbetts, P. Roos, Y. Taya, L. M. Karnitz and R. T. Abraham (1999) Inhibition of ATM and ATR kinase activities by the radiosensitizing agent, caffeine. Cancer Res. 59, 43754382.
  • 37
    Sarkaria, J. N., R. S. Tibbetts, E. C. Busby, A. P. Kennedy, D. E. Hill and R. T. Abraham (1998) Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Cancer Res. 58, 43754382.
  • 38
    Limoli, C. L., E. Giedzinski and J. E. Cleaver (2005) Alternative recombination pathways in UV-irradiated XP variant cells. Oncogene 24, 37083714.
  • 39
    Dunn, J., M. Potter, A. Rees and T. M. Runger (2006) Activation of the Fanconi anemia/BRCA pathway and recombination repair in the cellular responses to solar ultraviolet light. Cancer Res. 66, 1114011147.
  • 40
    Marti, T. M., E. Hefner, L. Feeney, V. Natale and J. E. Cleaver (2006) H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double strand breaks. Proc. Natl Acad. Sci. USA 103, 98919896.
  • 41
    Cleaver, J. E., J. Bartholomew, S. Char, E. Crowley, L. Feeney and C. L. Limoli (2002) Polymerase h and p53 jointly regulate cell survival, apoptosis and Mre11 recombination during S phase checkpoint arrest after UV irradiation. DNA Repair. 3, 117.
  • 42
    Hanasoge, S. and M. Ljungman (2007) H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase. Carcinogenesis 28, 22982304.
  • 43
    Matsumoto, M., K. Yaginuma, A. Igarashi, M. Imura, M. Hasegawa, K. Iwabuchi, T. Date, T. Mori, K. Ishizaki, K. Yamashita, M. Inobe and T. Matsunaga (2007) Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells. J. Cell Sci. 120, 11041112.
  • 44
    Cleaver, J. E., E. Hefner, R. R. Laposa, D. Karentz and T. Marti (2007) Cockayne syndrome exhibits dysregulation of p21 and other gene products that may be independent of transcription-coupled repair. Neuroscience 145, 13001308.
  • 45
    Cleaver, J. E. (1981) Sensitivity of excision repair in normal human, xeroderma pigmentosum variant and Cockayne’s syndrome fibroblasts to inhibition by cytosine arabinoside. J. Cell Physiol. 108, 163173.
  • 46
    Cleaver, J. E. (1969) Repair replication of mammalian cell DNA: Effects of compounds that inhibit DNA synthesis or dark repair. Radiat. Res. 37, 334348.
  • 47
    Regan, J. D., J. E. Trosko and W. L. Carrier (1968) Evidence for excision of ultraviolet-induced pyrimidine dimers from the DNA of human cells in vitro. Biophys. J. 8, 319325.
  • 48
    Ohmori, H., E. C. Friedberg, R. P. P. Fuchs, M. F. Goodman, F. Hanaoka, D. Hinkle, T. A. Kunkel, C. W. Lawrence, Z. Livneh, T. Nohmi, L. Prakash, S. Prakash, T. Todo, G. C. Walker, Z. Wang and R. Woodgate (2001) The Y-family of DNA polymerases. Mol. Cell 8, 78.
  • 49
    Woodgate, R. (2001) Evolution of the two-step model for UV-mutagenesis. Mutat. Res. 485, 8392.
  • 50
    Limoli, C. L., E. Giedzinski, W. F. Morgan and J. E. Cleaver (2000) Polymerase h deficiency in the XP variant uncovers an overlap between the S phase checkpoint and double strand break repair. Proc. Natl Acad. Sci. USA 97, 79397946.
  • 51
    Rizzo, J. L., J. Dunn, A. Rees and T. M. Rünger (2010) No formation of DNA double-strand breaks and no activation of recombination repair with UVA. J. Invest. Dermatol. 131, 11391148.
  • 52
    Squires, S., J. A. Coates, M. Goldberg, L. H. Toji, S. P. Jackson, D. J. Clarke and R. T. Johnson (2004) p53 prevents the accumulation of double-strand DNA breaks at stalled-replication forks induced by UV in human cells. Cell Cycle 3, 15431557.
  • 53
    Garinis, G. A., J. R. Mitchell, M. J. Moorhouse, K. Hanada, H. de Waard, D. Vandeputte, J. Jans, K. Brand, M. Smid, P. J. van der Spek, J. H. Hoeijmakers, R. Kanaar and G. T. van der Horst (2005) Transcriptome analysis reveals cyclobutane pyrimidine dimers as a major source of UV-induced DNA breaks. EMBO J. 24, 39523962.
  • 54
    Kratz, K., B. Schöpf, S. Kaden, A. Sendoel, R. Eberhard, C. Lademann, E. Cannavó, A. A. Sartori, M. O. Hengartner and J. Jiricny (2010) Deficiency of FANCD2-associated nuclease KIAA1018/FAN1 sensitizes cells to interstrand crosslinking agents. Cell 142, 7788.
  • 55
    Barnes, L., M. Dumas, M. Juan, E. Noblesse, A. Tesniere, S. Schnebert, B. Guillot and J. P. Molès (2010) GammaH2AX, an accurate marker that analyzes UV genotoxic effects on human keratinocytes and on human skin. Photochem. Photobiol. 86, 933941.
  • 56
    Painter, R. B. and B. R. Young (1975) X-ray-induced inhibition of DNA synthesis in Chinese hamster ovary, human HeLa, and mouse L cells. Radiat. Res. 64, 648656.
  • 57
    Lehmann, A. R., S. Kirk-Bell, C. A. Arlett, M. C. Paterson, P. H. M. Lohman, E. A. de Weerd-Kastelein and D. Bootsma (1975) Xeroderma pigmentosum cells with normal levels of excision repair have a defect on DNA synthesis after UV-irradiation. Proc. Natl Acad. Sci. USA 72, 219235.
  • 58
    Stiff, T., S. A. Walker, K. Cerosaletti, A. A. Goodarzi, E. Petermann, P. Concannon, M. O’Driscoll and P. A. Jeggo (2006) ATR-dependent phosphorylation and activation of ATM in response to UV treatment or replication fork stalling. EMBO J. 25, 57755782.
  • 59
    Smart, D. J., H. D. Halicka, G. Schmuck, F. Traganos, Z. Darzynkiewicz and G. M. Williams (2008) Assessment of DNA double-strand breaks and gammaH2AX induced by the topoisomerase II poisons etoposide and mitoxantrone. Mutat. Res. 641(1–2), 4347.
  • 60
    Donà, F., E. Prosperi, M. Savio, T. Coppa, A. I. Scovassi and C. Mondello (2008) Loss of histone H2AX increases sensitivity of immortalized mouse fibroblasts to the topoisomerase II inhibitor etoposide. Int. J. Oncol. 33, 613621.
  • 61
    Pospelova, T. V., Z. N. Demidenko, E. I. Bukreeva, V. A. Pospelov, A. V. Gudkov and M. V. Blagosklonny (2009) Pseudo-DNA damage response in senescent cells. Cell Cycle 8, 41124118.