title: PP4 is a gamma H2AX phosphatase required for recovery from the DNA damage checkpoint.
abstract: Phosphorylation of histone H2AX on Ser 139 (gammaH2AX) is one of the earliest events in the response to DNA double-strand breaks; however, the subsequent removal of gammaH2AX from chromatin is less understood, despite being a process tightly coordinated with DNA repair. Previous studies in yeast have identified the Pph3 phosphatase (the PP4C orthologue) as important for the dephosphorylation of gammaH2AX. By contrast, work in human cells attributed this activity to PP2A. Here, we report that PP4 contributes to the dephosphorylation of gammaH2AX, both at the sites of DNA damage and in undamaged chromatin in human cells, independently of a role in DNA repair. Furthermore, depletion of PP4C results in a prolonged checkpoint arrest, most likely owing to the persistence of mediator of DNA damage checkpoint 1 (MDC1) at the sites of DNA lesions. Taken together, these results indicate that PP4 is an evolutionarily conserved gammaH2AX phosphatase.
authors.affiliation: Centre for Systems Biology, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Nakada
authors.forename: Ginny I
authors.initials: GI
authors.lastname: Chen
authors.forename: Anne-Claude
authors.initials: AC
authors.lastname: Gingras
authors.forename: Daniel
authors.initials: D
authors.lastname: Durocher