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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >RPA phosphorylation facilitates mitotic exit in response to mitotic DNA damage
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RPA phosphorylation facilitates mitotic exit in response to mitotic DNA damage

机译：RPA磷酸化促进有丝分裂退出以响应有丝分裂DNA损伤

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摘要

Human replication protein A (RPA) becomes phosphorylated on the RPA2 subunit by cyclin B-Cdc2 during mitosis, although the functional role of this modification is unclear. We find that this modification stimulates RPA2 to become hyperphosphorylated in response to mitotic DNA damage caused by bleomycin treatment. Cells in which endogenous RPA2 was replaced by a mutant subunit lacking both Cdc2 sites had a significant defect in mitotic release into a 2N G_1 phase after exposure to bleomycin. An increased percentage of these mutant cells also was positive initially for cyclin B expression and BubR1 chromatin staining, indicative of an extended spindle assembly checkpoint. The mutant cells that experienced mitotic DNA damage also underwent apoptosis at higher levels than cells expressing the WT subunit. Even so, we did not find the mutation had any dramatic effects on the level of DNA repair in mitosis. Cells lacking ATM (a checkpoint factor and RPA2 kinase) also were severely defective in mitotic exit and were unable to support RPA hyperphosphorylation after mitotic DNA damage. Although checkpoint 1 effector kinase (Chk1) had a more complex role, inhibition of Chk1 activity with UCN-01 also reduced mitotic exit. Chk1 activation and mitotic RPA hyperphosphorylation were found to be independent events. Our results demonstrate that mitotic RPA hyperphosphorylation facilitates release of cells from a damaged mitosis into a 2N G_1 phase, thereby increasing cell viability.
机译：人类复制蛋白A（RPA）在有丝分裂过程中被细胞周期蛋白B-Cdc2磷酸化在RPA2亚基上，尽管这种修饰的功能作用尚不清楚。我们发现这种修饰刺激RPA2响应由博来霉素治疗引起的有丝分裂DNA损伤而变得超磷酸化。暴露于博来霉素后，内源性RPA2被缺少两个Cdc2位点的突变亚基替代的细胞在有丝分裂释放到2N G_1相中存在明显缺陷。这些突变细胞的百分比增加最初也对细胞周期蛋白B表达和BubR1染色质染色呈阳性，表明纺锤体装配检查点延长。经历有丝分裂DNA损伤的突变细胞也比表达WT亚基的细胞发生更高水平的凋亡。即使这样，我们仍未发现该突变对有丝分裂中的DNA修复水平有任何显着影响。缺乏ATM（检查点因子和RPA2激酶）的细胞在有丝分裂出口处也存在严重缺陷，并且在有丝分裂DNA损伤后无法支持RPA过度磷酸化。尽管检查点1效应激酶（Chk1）的作用更为复杂，但用UCN-01抑制Chk1活性也减少了有丝分裂的退出。发现Chk1激活和有丝分裂RPA过度磷酸化是独立的事件。我们的结果表明，有丝分裂RPA过度磷酸化促进细胞从受损的有丝分裂释放到2N G_1相，从而增加细胞活力。

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