Tyrosine Dephosphorylation of H2AX Modulates Apoptosis and Survival Decisions

Cook, Peter J; Ju, Bong Gun; Telese, Francesca; Wang, Xiangting; Glass, Christopher K.; Rosenfeld, Michael G.

doi:10.1038/nature07849

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Tyrosine Dephosphorylation of H2AX Modulates Apoptosis and Survival Decisions

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Author(s): Peter J. Cook ¹ ^, ² , Bong Gun Ju ¹ ^, ³ , Francesca Telese ¹ , Xiangting Wang ¹ , Christopher K. Glass ⁴ , Michael G. Rosenfeld ¹ ^, ⁴

Publication date (Electronic): 22 February 2009

Journal: Nature

Keywords: Eya, H2AX, DNA repair, apoptosis

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Abstract

Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. While the regulatory mechanisms and signaling pathways controlling DNA repair and apoptosis are well characterized, the precise molecular strategies that determine the ultimate choice of DNA repair and survival or apoptotic cell death remain incompletely understood. Here, we report that a protein tyrosine phosphatase, Eya, is involved in promoting efficient DNA repair rather than apoptosis in response to genotoxic stress in specific tissue/cell types by executing a damage-signal dependent dephosphorylation of an H2AX C-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of γH2AX and allows it to function as an active determinant of repair/survival versus apoptotic responses to DNA damage, revealing an additional phosphorylation-dependent mechanism that modulates survival/apoptotic decisions during mammalian organogenesis.

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MDC1 directly binds phosphorylated histone H2AX to regulate cellular responses to DNA double-strand breaks.

Manuel Stucki, Julie A. Clapperton, Duaa Mohammad … (2005)

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. Loss of H2AX causes radiosensitivity, genome instability, and DNA double-strand-break repair defects, yet the mechanisms underlying these phenotypes remain obscure. Here, we demonstrate that mammalian MDC1/NFBD1 directly binds to phospho-H2AX (gammaH2AX) by specifically interacting with the phosphoepitope at the gammaH2AX carboxyl terminus. Moreover, through a combination of biochemical, cell-biological, and X-ray crystallographic approaches, we reveal the molecular details of the MDC1/NFBD1-gammaH2AX complex. These data provide compelling evidence that the MDC1/NFBD1 BRCT repeat domain is the major mediator of gammaH2AX recognition following DNA damage. 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. Thus, binding of MDC1/NFBD1 to gammaH2AX plays a central role in the mammalian response to DNA damage.

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Genomic instability in mice lacking histone H2AX.

Arkady Celeste, Simone Petersen, Peter J Romanienko … (2002)

Higher order chromatin structure presents a barrier to the recognition and repair of DNA damage. Double-strand breaks (DSBs) induce histone H2AX phosphorylation, which is associated with the recruitment of repair factors to damaged DNA. To help clarify the physiological role of H2AX, we targeted H2AX in mice. Although H2AX is not essential for irradiation-induced cell-cycle checkpoints, H2AX-/- mice were radiation sensitive, growth retarded, and immune deficient, and mutant males were infertile. These pleiotropic phenotypes were associated with chromosomal instability, repair defects, and impaired recruitment of Nbs1, 53bp1, and Brca1, but not Rad51, to irradiation-induced foci. Thus, H2AX is critical for facilitating the assembly of specific DNA-repair complexes on damaged DNA.

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Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks.

Arkady Celeste, Oscar Fernandez-Capetillo, Michael J. Kruhlak … (2003)

Histone H2AX is rapidly phosphorylated in the chromatin micro-environment surrounding a DNA double-strand break (DSB). Although H2AX deficiency is not detrimental to life, H2AX is required for the accumulation of numerous essential proteins into irradiation induced foci (IRIF). However, the relationship between IRIF formation, H2AX phosphorylation (gamma-H2AX) and the detection of DNA damage is unclear. Here, we show that the migration of repair and signalling proteins to DSBs is not abrogated in H2AX(-/-) cells, or in H2AX-deficient cells that have been reconstituted with H2AX mutants that eliminate phosphorylation. Despite their initial recruitment to DSBs, numerous factors, including Nbs1, 53BP1 and Brca1, subsequently fail to form IRIF. We propose that gamma-H2AX does not constitute the primary signal required for the redistribution of repair complexes to damaged chromatin, but may function to concentrate proteins in the vicinity of DNA lesions. The differential requirements for factor recruitment to DSBs and sequestration into IRIF may explain why essential regulatory pathways controlling the ability of cells to respond to DNA damage are not abolished in the absence of H2AX.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 13 May 2009

Publication date (Electronic): 22 February 2009

Publication date (Print): 2 April 2009

Publication date PMC-release: 2 October 2009

Volume: 458

Issue: 7238

Pages: 591-596

Affiliations

[1 ] Howard Hughes Medical Institute, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093

[2 ] Department of Biology Graduate Program, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093

[3 ] Department of Life Science, Sogang University, Seoul 121-742, Korea

[4 ] Department of Cellular and Molecular Medicine, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093

Author notes

[# ]To whom correspondence should be addressed: mrosenfeld@ 123456ucsd.edu

[*]

Denote equal contribution

Article

Manuscript ID: nihpa103033

DOI: 10.1038/nature07849

PMC ID: 2692521

PubMed ID: 19234442

SO-VID: 406e8684-628d-49ae-b660-31b34d2a520d