Polo-like kinase 1 inhibits DNA damage response during mitosis.
Polo-like kinase 1 inhibits DNA damage response during mitosis.
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DOI：
10.4161/15384101.2014.977067
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Macurek L
中科院分区：
文献类型：
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作者：
Benada J;Burdová K;Lidak T;von Morgen P;Macurek L
为了应对基因毒性应激，细胞通过激活保守的 DNA 损伤反应 (DDR) 途径来保护其基因组完整性，该途径协调 DNA 修复和整个细胞周期的进展。 ATM 激酶和 RNF8/RNF168 泛素连接酶对 DNA 损伤侧翼的染色质进行广泛修饰，从而能够招募各种修复因子。其中BRCA1和53BP1分别是同源重组和非同源末端连接所必需的。虽然 DDR 机制在间期细胞中的了解相对较好，但对有丝分裂期间 DDR 的组织了解相对较少。尽管 ATM 可以在有丝分裂细胞中被激活，但直到细胞退出有丝分裂时，53BP1 才会被招募到染色质。在这里，我们报道了 Plk1 和 Cdk1 对 53BP1 的有丝分裂磷酸化，这削弱了 53BP1 结合泛素化 H2A 和正确定位到 DNA 损伤位点的能力。 53BP1 在 S1618 处的磷酸化发生在着丝粒和细胞质中，并且仅限于有丝分裂细胞。 53BP1 和 Plk1 之间的相互作用取决于 Cdk1 的活性。我们认为 Cdk1 和 Plk1 的活性可以在有丝分裂期间对 53BP1 功能进行时空控制抑制。
In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and non-homologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.