DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1

Fernández-Capetillo, Óscar; Chen, Hua Tang; Celeste, Arkady; Ward, Irene M.; Romanienko, Peter; Morales, Julio C.; Naka, Kazuhito; Xia, Zhengfang; Camerini‐Otero, R. Daniel; Motoyama, Noboru; Carpenter, Phillip B.; Bonner, William M.; Chen, Junjie; Nussenzweig, André

doi:10.1038/ncb884

Cited by 620 publications

(540 citation statements)

References 25 publications

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“…Although Chk2 is phosphorylated by ATM in response to DSBs, we and others have observed that Chk2-deficient cells effect G2/M checkpoint arrest proficiently after IR (although they have been reported in other studies to be defective in the maintenance of this arrest) [27,28](Deckbar, manuscript submitted) . The failure of Chk2-deficient cells to arrest is most likely due to overlapping functions of Chk1 and Chk2 [29].…”

Section: Apoptosismentioning

confidence: 70%

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

2006

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Article (Unspecified) http://sro.sussex.ac.uk Jeggo, P. A. and Lobrich, M. (2006) Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability. DNA Repair, 5 (9-10). pp. 1192 -1198 . ISSN 1568 This version is available from Sussex Research Online: http://sro.sussex.ac.uk/587/ This document is made available in accordance with publisher policies and may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the URL above for details on accessing the published version. Copyright and reuse:Sussex Research Online is a digital repository of the research output of the University.Copyright and all moral rights to the version of the paper presented here belong to the individual author(s) and/or other copyright owners. To the extent reasonable and practicable, the material made available in SRO has been checked for eligibility before being made available.Copies of full text items generally can be reproduced, displayed or performed and given to third parties in any format or medium for personal research or study, educational, or not-for-profit purposes without prior permission or charge, provided that the authors, title and full bibliographic details are credited, a hyperlink and/or URL is given for the original metadata page and the content is not changed in any way. DNA damage response mechanisms encompass pathways of DNA repair, cell cycle checkpoint arrest and apoptosis. Together, these mechanisms function to maintain genomic stability in the face of exogenous and endogenous DNA damage. ATM is activated in response to double strand breaks and initiates cell cycle checkpoint arrest. Recent studies in human fibroblasts have shown that ATM also regulates a mechanism of end-processing that is required for a component of double strand break repair. Human fibroblasts rarely undergo apoptosis after ionising radiation and, therefore, apoptosis is not considered in our review. The dual function of ATM raises the question as to how the two processes, DNA repair and checkpoint arrest, interplay to maintain genomic stability. In this review, we consider the impact of ATM's repair and checkpoint functions to the maintenance of genomic stability following irradiation in G2. We discuss evidence that ATM's repair function plays little role in the maintenance of genomic stability following exposure to ionising radiation. ATM's checkpoint function has a bigger impact on genomic stability but strikingly the two damage response pathways co-operate in a more than additive manner. In contrast, ATM's repair function is important for survival post irradiation.Introduction.

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Section: Apoptosismentioning

confidence: 70%

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

2006

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“…Based on its very early appearance, it was assumed that g-H2A.X is a very early response to DSBs and, hence, required for the recruitment of DSB signaling and repair proteins to the sites of DSBs. This hypothesis was supported by data showing that the accumulation in DSB repair foci of numerous repair proteins including 53BP1, BRCA1, and MDC1 is impaired in H2A.X null cells [Bassing et al, 2002;Celeste et al, 2002;Fernandez-Capetillo et al, 2002;Stewart et al, 2003]. In contrast, another study from the Nussenzweig lab showed that H2A.X is dispensable for the initial recruitment of these proteins to the sites of DSBs in MEFs lacking H2A.X expression [Celeste et al, 2003b].…”

Section: C-h2ax and The Dsb Responsementioning

confidence: 90%

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

Ismail

Hendzel

2007

Environ and Mol Mutagen

101

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In recent years, several histone modifications have been implicated in the cellular response to DNA double-strand breaks (DSBs). One of the best characterized histone modifications important in DSB repair is the phosphorylation of histone H2A variant, H2A.X. In response to DSBs, H2A.X is phosphorylated and this phosphorylation is required for DSB signaling and the retention of repair proteins at the break site. Despite the existing picture that the function of H2A.X is to promote DNA repair, very recent data suggest that the phosphorylation of histone H2A.X has additional functions. This is analogous to histone H3 phosphorylation on serine 10, which participates in seemingly incompatible functions-transcriptional activation and mitosis. In this review, we discuss the role of histone H2A.X in maintaining genomic stability and review emerging evidence that histone H2A.X is multifunctional. Environ. Mol. Mutagen. 49:73-82, 2008. V V C 2007 Wiley-Liss, Inc.

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“…In concordance with these data, recent studies showed that many proteins that are involved in DNA repair and that are activated by ATM/ATR are overexpressed in the nuclei of senescent cells and form DNA damage foci at dysfunctional telomeres (8,54) and intragenomic double-strand breaks (45). These proteins include phosphorylated H2AX (␥-H2AX), a common marker of cellular double-strand breaks that in turn promotes the assembly of several checkpoint and DNA repair factors (e.g., 53BP1, MDC1, and NBS1) at the site of DNA damage (17,52). To explore whether the dysfunctional telomeres and doublestrand breaks in senescent cells elicit a constitutive DNA damage signal irrespective of external factors, the localization and expression of these proteins (␥-H2AX, 53BP1, MDC1, and NBS1) in early-and late-passage HK1 cells under serial passage, serum starvation, and serum restimulation were monitored.…”

Section: Resultsmentioning

confidence: 99%

Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

Satyanarayana¹,

Greenberg²,

Schaetzlein³

et al. 2004

Molecular and Cellular Biology

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DNA damage-induced G2–M checkpoint activation by histone H2AX and 53BP1

Cited by 620 publications

References 25 publications

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

Contribution of DNA repair and cell cycle checkpoint arrest to the maintenance of genomic stability

The γ‐H2A.X: Is it just a surrogate marker of double‐strand breaks or much more?

Mitogen Stimulation Cooperates with Telomere Shortening To Activate DNA Damage Responses and Senescence Signaling

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