Polo-like kinase 1 mediates BRCA1 phosphorylation and recruitment at DNA double-strand breaks.
Polo-like kinase 1 mediates BRCA1 phosphorylation and recruitment at DNA double-strand breaks.
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DOI：
10.18632/oncotarget.6825
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发表时间：
2016-01-19
期刊：
影响因子：
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通讯作者：
Larminat F
中科院分区：
文献类型：
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作者：
Chabalier-Taste C;Brichese L;Racca C;Canitrot Y;Calsou P;Larminat F
DNA双链断裂（DSB）在DNA复制过程中引起的和外源压力的准确修复是维持基因组完整性的关键。越来越多的证据表明，Polo样激酶1（Plk 1）在细胞增殖中起着许多关键作用，可以直接参与DSB修复的调节。在这项研究中，我们表明Plk1调节BRCA1，一个关键的介质蛋白，需要有效地修复DSB通过同源重组（HR）。在DSB诱导后，BRCA 1集中在损伤部位的独特的大核灶中，在那里积累了多种DNA修复因子。首先，我们发现，在DNA损伤前不久抑制Plk1使细胞对电离辐射敏感，并减少DSB修复HR.Second，我们提供的证据表明，BRCA1病灶的形成减少DSB诱导Plk1被抑制或耗尽时。第三，我们确定BRCA1作为一种新的Plk1底物，并确定Ser1164是Plk1在体外的主要磷酸化位点。在细胞中，BRCA 1上Plk 1位点的突变显著延迟了DSB后BRCA 1病灶的形成，重现了Plk 1抑制后观察到的表型。我们的数据，然后分配一个关键功能Plk1在BRCA1灶形成DSB，强调Plk1在人类细胞的HR修复的重要性。
Accurate repair of DNA double-strand breaks (DSB) caused during DNA replication and by exogenous stresses is critical for the maintenance of genomic integrity. There is growing evidence that the Polo-like kinase 1 (Plk1) that plays a number of pivotal roles in cell proliferation can directly participate in regulation of DSB repair. In this study, we show that Plk1 regulates BRCA1, a key mediator protein required to efficiently repair DSB through homologous recombination (HR). Following induction of DSB, BRCA1 concentrates in distinctive large nuclear foci at damage sites where multiple DNA repair factors accumulate. First, we found that inhibition of Plk1 shortly before DNA damage sensitizes cells to ionizing radiation and reduces DSB repair by HR. Second, we provide evidence that BRCA1 foci formation induced by DSB is reduced when Plk1 is inhibited or depleted. Third, we identified BRCA1 as a novel Plk1 substrate and determined that Ser1164 is the major phosphorylation site for Plk1 in vitro. In cells, mutation of Plk1 sites on BRCA1 significantly delays BRCA1 foci formation following DSB, recapitulating the phenotype observed upon Plk1 inhibition. Our data then assign a key function to Plk1 in BRCA1 foci formation at DSB, emphasizing Plk1 importance in the HR repair of human cells.