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PMID: 19234442 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions.

Nature ·Vol. 458 ·No. 7238 ·2009-04-02 ·Pages 591-6

Cook PJ, Ju BG, Telese F, Wang X, Glass CK, Rosenfeld MG

Abstract

Life and death fate decisions allow cells to avoid massive apoptotic death in response to genotoxic stress. Although the regulatory mechanisms and signalling 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 mammalian embryonic kidney cells by executing a damage-signal-dependent dephosphorylation of an H2AX carboxy-terminal tyrosine phosphate (Y142). This post-translational modification determines the relative recruitment of either DNA repair or pro-apoptotic factors to the tail of serine phosphorylated histone H2AX (gamma-H2AX) 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.

MeSH Terms
Animals Apoptosis Ataxia Telangiectasia Mutated Proteins Cell Cycle Proteins/metabolism Cell Line Cell Survival DNA Damage DNA Repair DNA-Binding Proteins/deficiency,genetics,metabolism Histones/deficiency,genetics,metabolism Humans Intracellular Signaling Peptides and Proteins/deficiency,genetics,metabolism Mice Nuclear Proteins/deficiency,genetics,metabolism Phosphorylation Phosphotyrosine/metabolism Protein Binding Protein Serine-Threonine Kinases/metabolism Protein Tyrosine Phosphatases/deficiency,genetics,metabolism Substrate Specificity Tumor Suppressor Proteins/metabolism Tyrosine/metabolism
Chemicals
Cell Cycle Proteins DNA-Binding Proteins H2AX protein, human H2AX protein, mouse Histones Intracellular Signaling Peptides and Proteins Nuclear Proteins Tumor Suppressor Proteins Phosphotyrosine Tyrosine ATM protein, human ATR protein, human Ataxia Telangiectasia Mutated Proteins Atm protein, mouse Protein Serine-Threonine Kinases EYA1 protein, human EYA3 protein, human Eya1 protein, mouse Protein Tyrosine Phosphatases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Cook Peter J
Howard Hughes Medical Institute School of Medicine, University of California, San Diego, California 92037, USA.
Ju Bong Gun
Telese Francesca
Wang Xiangting
Glass Christopher K
Rosenfeld Michael G
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature07849
Published
2009-04-02
Epub
2009-00-22
Pages
591-6
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2692521
Subset
IM
Grants
NIDDK NIH HHS · R01 DK039949-18 · United States
NCI NIH HHS · R01 CA097134-07 · United States
NHLBI NIH HHS · R01 HL065445-09 · United States
NIDDK NIH HHS · R01 DK039949-17S1 · United States
NINDS NIH HHS · R01 NS034934 · United States
NINDS NIH HHS · R01 NS034934-18 · United States
NHLBI NIH HHS · R01 HL065445 · United States
NHLBI NIH HHS · R01 HL065445-08 · United States
NCI NIH HHS · R01 CA097134 · United States
Howard Hughes Medical Institute · United States
NINDS NIH HHS · R01 NS034934-19 · United States
NIDDK NIH HHS · R01 DK039949 · United States
NINDS NIH HHS · R01 NS034934-20A1 · United States
NCI NIH HHS · R01 CA097134-06A1 · United States
Corrections
CommentIn
PMID: 19340068
External Links
PubMed source DOI: 10.1038/nature07849 PMC Full Text View journal details
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