Histone H2AX

Phosphorylation of H2AX appears to be the product of three regulated signaling pathways involving the kinases DNA-PK, ATM (Ataxia Telengiectasia Mutated), and ATR (AT-Rad3 related). These enzymes display both redundancy and 

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Although the effects of y-H2AX foci are still poorly understood, two theories have been proposed that may not be mutually exclusive [17,18], The first model suggests that the post-translational modification may impart structural transitions to DSB domains, and the second implicates the histone variant as a signaling intermediate in the repair pathway. 

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Furuta T, Takemura H, Liao ZY, Aune GJ, Redon C, Sedelnikova OA, et al. Phosphorylation of histone H2AX and activation of Mrell, Rad50, and Nbsl in response to replication-dependent DNA double-strand breaks induced by mammalian DNA topoisomerase I cleavage complexes. J. Biol. Chem. 2003 May 30 278(22) 20303-12. 

Huang X, Okafuji M, Traganos F, Luther E, Holden E, Darzynkiewicz Z. Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin. Cytometry A. 2004 Apr 58(2) 99-110. 

Bassing CH, Suh H, Ferguson DO, Chua KF, Manis J, Eckersdorff M, Gleason M, Bronson R, Lee C, Alt FW (2003) Histone H2AX a dosage-dependent suppressor of oncogenic translocations and tumors. Cell 114 359-370... 

Tagami H, Ray-Gallet D, Almouzni G, Nakatani Y (2004) Histone H3.1 and H3.3 complexes mediate nucleosome assembly pathways dependent or independent of DNA synthesis. Cell 116 51-61 Taneja N, Davis M, Choy JS, Beckett MA, Singh R, Kron SJ, Weichselbaum RR (2004) Histone H2AX phosphorylation as a predictor of radiosensitivity and target for radiotherapy. J Biol Chem 279 2273-2280... 

Sedelnikova OA, Pilch DR, Redon C, Bonner WM (2003) Histone H2AX in DNA damage and repair. Cancer Biol Ther 2 233-235... 

Eernandez-Capetillo O, Allis CD, Nussenzweig A (2004) Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med 199(12) 1671—1677 Eernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC, Naka K, Xia Z, Camerini-Otero RD, Motoyama N, Carpenter PB, Bonner WM, Chen J, Nussenzweig A (2002) DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1. Nat Cell Biol 4(12) 993-997... 

Kurose A, Tanaka T, Huang X, Halicka HD, Traganos F, Dai W, Darzynkiewicz Z (2005) Assessment of ATM phosphorylation on Ser-1981 induced by DNA topoisomerase I and II inhibitors in relation to Ser-139-histone H2AX phosphorylation, cell cycle phase, apoptosis. Cytometry A 68(1) 1—9... 

Mukherjee B, Kessinger C, Kobayashi J, Chen BP, Chen DJ, Chatterjee A, Burma S (2006) DNA-PK phosphorylates histone H2AX during apoptotic DNA fragmentation in mammalian cells. DNA Repair (Amst) 5(5) 575-590... 

Ward IM, Chen J (2001) Histone H2AX is phosphorylated in an ATR-dependent manner in response to repUcational stress. J Biol Chem 276(51) 47759 7762 Wei Y, Mizzen CA, Cook RG, Gorovsky MA, AlUs CD (1998) Phosphorylation of histone H3 at serine 10 is correlated with chromosome condensation during mitosis and meiosis in Tetrahymena. Proc Natl Acad Sci USA 95(13) 7480-7484... 

SI39 (for mammals). The responsible kinases are members from phosphatidyli-nositol 3-kinase (PI3K)-like family kinases, which include ataxia telangiectasia mutated (ATM), AT-related (ATR), and DNA dependent protein kinase (DNA-PK) (Burma et al, 2001 Stiff et al, 2004 van Attikum and Gasser, 2005). Histone H2AX phosphorylation is directly related to repair of damaged chromatin (for details see chapter on Role of histone phosphorylation in chromatin dynamics and its implication in diseases ). 

Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276 42462-42467... 

Pauli, T.T., Rogakou, E.P., Yamazaki, V., Kirchgessner, C.U., Gellert, M., and Bonner, W.M. (2000) A critical role for histone H2AX in recruitment of repair factors to nuclear foci after DNA damage. Curr. Biol. 10, 886-895. 

Figure 1 Sensing of DSBs by the ATM checkpoint. DSBs trigger the autophosphorylation of ATM and transform the inactive ATM oligomers to active ATM monomers. The MRN complex is important for the recruitment and the activation of ATM at DSBs. ATM phosphorylates the histone H2AX adjacent to the DSBs, which in turn recruits the mediator Mdcl and brings in additional ATM molecules.

Stuck M, Clapperton JA, Mohammad D, Yaffe MB, Smerdon SJ, Jackson SP. MDCl directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks. Cell 2005 123(7) 1213-1226. 

Ward, I. M., Chen, J. (2001). Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. The Journal of Biological Chemistry, 276, 47759—47762. 

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