Tyrosine dephosphorylation of H2AX modulates apoptosis and survival decisions

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.

Pyk2 cytonuclear localization: mechanisms and regulation by serine dephosphorylation

“…The autophosphorylated, active form of Pyk2 accumulates in the nucleus of depolarized neurons [20], although Pyk2 nuclear accumulation is independent of its autophosphorylation and kinase activity ( [20] and present study). Pyk2 could directly regulate tyrosine phosphorylated resident proteins of the nucleus such as histone variant H2AX [51] or H3/H4 [52]. Pyk2 associates with Src-family kinases, which localize to the nucleus in specific conditions, regulating euchromatin decondensation [53] and protection against oxidative stress through phosphorylation of Nrf2 by Fyn [54,55].…”

The role of nuclear organization in cancer

“…DSBs are detected by the Mre11-Rad50-Nbs1 complex, which then recruits the ataxia-telangiectasia mutated (ATM) kinase, and post-translational modifications of the histone variant H2A.X occur in the surrounding chromatin [37,38]. These modifications act as a switch, either to promote recruitment of the repair machinery or to induce apoptosis.…”

Dual recognition of phosphoserine and phosphotyrosine in histone variant H2A.X by DNA damage response protein MCPH1

“…In response to DNA damage, Tyr142 was found to transition from a phosphorylated (pTyr142) to a nonphosphorylated state in an Eya1/3 phosphatase-dependent manner (6)(7)(8). Whereas the dephosphorylation of pTyr142 is gradual, the phosphorylation of Ser139 is prompt, and the overlap in the two processes is thought to give rise to the doubly phosphorylated (pSer139, pTyr142) H2A.X state (di-γH2A.X) following genotoxic insult (6,7). The existence of di-γH2A.X and proteins that recognize this state remain open questions in the field.…”