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Sci. Signal., 7 April 2009
Vol. 2, Issue 65, p. ec126
[DOI: 10.1126/scisignal.265ec126]

EDITORS' CHOICE

Cell Biology Repair or Die

Wei Wong

Science Signaling, AAAS, Washington, DC 20005, USA

Originally identified as a transcription factor, Eyes absent (Eya) is also a tyrosine phosphatase, and its absence is associated with increased apoptosis. Cook et al. (see Lukas and Bartek) observed increased immunostaining for the Ser139-phosphorylated histone variant H2AX [a modification that enables Ser139 to act as a binding site for DNA repair factors, such as MDC1 (mediator of DNA damage checkpoint protein 1)] in Eya1–/– mouse embryo kidneys. Eya1 and Eya3 interacted and colocalized with H2AX at sites of double-stranded breaks in nuclei in human embryonic kidney (HEK) 293T cells exposed to ionizing radiation, but not in unexposed cells. This interaction required phosphorylation of Eya3 at Ser219 by the DNA-damage response kinases ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The H2AX C terminus is phosphorylated at Tyr142 as well as Ser139. Tyr142 phosphorylation decreased when cells were exposed to three different DNA-damaging treatments; this dephosphorylation was mediated by wild-type Eya1 and Eya3 but not catalytically inactive mutants. The phosphorylation status of Tyr142 determined whether irradiation induced phosphorylation of Ser139 and whether DNA repair or proapoptotic factors were recruited to H2AX. A peptide corresponding to the H2AX C terminus that was phosphorylated at Ser139 but not Tyr142 interacted with MDC1 and other DNA repair factors. Accordingly, knockdown of Eya3 by small interfering RNAs (siRNAs) (which would be expected to increase Tyr142 phosphorylation of H2AX) prevented the irradiation-induced interaction between MDC1 and H2AX. In contrast, a H2AX C terminus peptide that was phosphorylated at both residues associated with the proapoptotic c-Jun N-terminal kinase 1 (JNK1). JNK1 was recruited to H2AX by Fe65, a protein that may promote apoptosis; Fe65 did not interact as strongly with a Tyr142->Phe142 H2AX mutant compared to wild-type. The authors propose a model in which dephosphorylation of Tyr142 in H2AX by Eya recruits DNA damage repair factors and promotes cell survival, whereas maintenance of phosphorylation of Tyr142 in H2AX recruits proapoptotic factors and promotes cell death.

P. J. Cook, B. G. Ju, F. Telese, X. Wang, C. K. Glass, M. G. Rosenfeld, Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions. Nature 458, 591–596 (2009). [PubMed]

J. Lukas, J. Bartek, DNA repair: New tales of an old tail. Nature 458, 581–583 (2009). [PubMed]

Citation: W. Wong, Repair or Die. Sci. Signal. 2, ec126 (2009).



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