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首页> 外文期刊>Molecular cell >Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks
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Dephosphorylation Enables the Recruitment of 53BP1 to Double-Strand DNA Breaks

机译：脱磷酸使53BP1可以招募到双链DNA断裂

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摘要

Excluding 53BP1 from chromatin is required to attenuate the DNA damage response during mitosis, yet the functional relevance and regulation of this exclusion are unclear. Here we show that 53BP1 is phosphorylated during mitosis on two residues, T1609 and S1618, located in its well-conserved ubiquitination-dependent recruitment (UDR) motif. Phosphorylating these sites blocks the interaction of the UDR motif with mononuclesomes containing ubiquitinated histone H2A and impedes binding of 53BP1 to mitotic chromatin. Ectopic recruitment of 53BP1-T1609A/S1618A to mitotic DNA lesions was associated with significant mitotic defects that could bereversed by inhibiting nonhomologous end-joining. We also reveal that protein phosphatase complex PP4C/R3β dephosphorylates T1609 and S1618 toallow the recruitment of 53BP1 to chromatin in G1 phase. Our results identify key sites of 53BP1 phosphorylation during mitosis, identify the counteracting phosphatase complex that restores the potential for DDR during interphase, and establish the physiological importance of this regulation.
机译：需要从染色质中排除53BP1来减弱有丝分裂期间的DNA损伤反应，但是尚不清楚该排斥的功能相关性和调节。在这里，我们显示53BP1在有丝分裂期间在两个残基T1609和S1618上被磷酸化，这两个残基位于其保存完好的泛素依赖性依赖募集（UDR）主题中。使这些位点磷酸化会阻止UDR基序与包含泛素化的组蛋白H2A的单核小体的相互作用，并阻碍53BP1与有丝分裂染色质的结合。 53BP1-T1609A / S1618A异位募集至有丝分裂DNA损伤与明显的有丝分裂缺陷相关，可以通过抑制非同源末端连接来逆转。我们还揭示了蛋白磷酸酶复合物PP4C /R3β使T1609和S1618去磷酸化，从而允许在G1期将53BP1募集到染色质上。我们的结果确定了有丝分裂期间53BP1磷酸化的关键位点，确定了在相间期恢复DDR潜力的抗磷酸酶复合物，并确立了这种调节的生理重要性。

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