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Critical Function of γH2A in S-Phase


ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related) are evolutionary conserved protein kinases that phosphorylate the carboxyl-tail of histone H2AX in chromatin flanking DNA lesions. Phosphorylated histone H2AX (aka γH2AX) tethers important DNA damage response (DDR) proteins to DNA double-strand breaks but its function during DNA replication is unclear. A novel genetic screen reveals that a partial defect in Replication Factor C (RFC) creates a critical requirement for γH2AX in fission yeast. These studies indicate that γH2AX stabilizes replication forks by recruiting Brc1 when RFC is unable to load the DNA clamp known as proliferating cell nuclear antigen (PCNA) onto duplex DNA. Surprisingly, this activity of γH2AX is more critical than ATM/ATR-mediated activation of the checkpoint kinase Chk1 and Chk2.


Vyšlo v časopise: Critical Function of γH2A in S-Phase. PLoS Genet 11(9): e32767. doi:10.1371/journal.pgen.1005517
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005517

Souhrn

ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3 related) are evolutionary conserved protein kinases that phosphorylate the carboxyl-tail of histone H2AX in chromatin flanking DNA lesions. Phosphorylated histone H2AX (aka γH2AX) tethers important DNA damage response (DDR) proteins to DNA double-strand breaks but its function during DNA replication is unclear. A novel genetic screen reveals that a partial defect in Replication Factor C (RFC) creates a critical requirement for γH2AX in fission yeast. These studies indicate that γH2AX stabilizes replication forks by recruiting Brc1 when RFC is unable to load the DNA clamp known as proliferating cell nuclear antigen (PCNA) onto duplex DNA. Surprisingly, this activity of γH2AX is more critical than ATM/ATR-mediated activation of the checkpoint kinase Chk1 and Chk2.


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