Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition

0354924 - ÚMG 2011 RIV GB eng J - Journal Article
Macůrek, Libor - Lindqvist, A. - Voets, O. - Kool, J. - Vos, H.R. - Medema, R.H.
Wip1 phosphatase is associated with chromatin and dephosphorylates gammaH2AX to promote checkpoint inhibition.
Oncogene. Roč. 29, č. 15 (2010), s. 2281-2291. ISSN 0950-9232. E-ISSN 1476-5594
R&D Projects: GA ČR GPP305/10/P420
Institutional research plan: CEZ:AV0Z50520514
Keywords : DNA damage * checkpoint * phosphatase
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 7.414, year: 2010

DNA double-stranded breaks (DSBs) elicit a checkpoint response that causes a delay in cell cycle progression and enables DNA repair. Phosphorylated form of the histone H2AX (called gamma-H2AX) serves as an essential platform for recruitment and retention of additional components of the checkpoint signaling cascade (such as MDC1 and 53BP1) in the chromatin region flanking the DSB. Here we demonstrate that the Wip1 phosphatase is bound to chromatin and directly dephosphorylates gamma-H2AX. Cells depleted of Wip1 fail to dephosphorylate gamma-H2AX during checkpoint recovery. Conversely, premature activation of Wip1 leads to displacement of MDC1 from damage foci and prevents activation of the checkpoint. Taken together, our data demonstrate that Wip1 plays an essential role in dephosphorylation of gamma-H2AX in order to silence the checkpoint and restore chromatin structure once DNA damage is repaired.
Permanent Link: http://hdl.handle.net/11104/0193819