PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle.
PLK1 regulates the PrimPol damage tolerance pathway during the cell cycle.
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PLK1在细胞周期中调节PrimPol损伤耐受途径。
DOI：
10.1126/sciadv.abh1004
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发表时间：
2021-12-03
期刊：
影响因子：
13.6
通讯作者：
Doherty AJ
中科院分区：
文献类型：
--
作者：
Bailey LJ;Teague R;Kolesar P;Bainbridge LJ;Lindsay HD;Doherty AJ
PrimPol受PLK1磷酸化调控，以限制重复启动，防止基因组不稳定。复制压力和DNA损伤阻碍了复制分叉，阻碍了基因组合成。在S阶段，损伤耐受通路允许病变旁路，以确保有效的基因组复制。在人类细胞中，一个这样的途径是由PrimPol(PrimPol)介导的重启。然而，人们对PrimPol的监管机制知之甚少。在这里，我们证明了PrimPol是由Polo-like kinase1(PLK1)在PrimPol的RPA结合基序之间的保守残基上磷酸化的。这种磷酸化在整个细胞周期中被不同地修饰，从而防止PrimPol异常地重新聚集到染色质。复制压力下，磷酸化也可以延迟或逆转。PrimPol缺乏PLK1依赖的调控会导致染色体断裂、微核等表型，并导致喜树碱、奥拉帕利和UV-C治疗后存活率下降。总之，这些发现确立了解除调控的重新启动导致基因组不稳定，强调了在分叉失速之后和整个细胞周期中调节这一损伤耐受途径的重要性。
PrimPol is regulated by PLK1 phosphorylation to restrict repriming and prevent genomic instability. Replication stress and DNA damage stall replication forks and impede genome synthesis. During S phase, damage tolerance pathways allow lesion bypass to ensure efficient genome duplication. One such pathway is repriming, mediated by Primase-Polymerase (PrimPol) in human cells. However, the mechanisms by which PrimPol is regulated are poorly understood. Here, we demonstrate that PrimPol is phosphorylated by Polo-like kinase 1 (PLK1) at a conserved residue between PrimPol’s RPA binding motifs. This phosphorylation is differentially modified throughout the cell cycle, which prevents aberrant recruitment of PrimPol to chromatin. Phosphorylation can also be delayed and reversed in response to replication stress. The absence of PLK1-dependent regulation of PrimPol induces phenotypes including chromosome breaks, micronuclei, and decreased survival after treatment with camptothecin, olaparib, and UV-C. Together, these findings establish that deregulated repriming leads to genomic instability, highlighting the importance of regulating this damage tolerance pathway following fork stalling and throughout the cell cycle.
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影响因子：
16
作者：
Genois MM;Gagné JP;Yasuhara T;Jackson J;Saxena S;Langelier MF;Ahel I;Bedford MT;Pascal JM;Vindigni A;Poirier GG;Zou L
通讯作者：
Zou L
影响因子：
7.2
作者：
Goodman MF;Woodgate R
通讯作者：
Woodgate R
影响因子：
16
作者：
Bianchi, Julie;Rudd, Sean G.;Jozwiakowski, Stanislaw K.;Bailey, Laura J.;Soura, Violetta;Taylor, Elaine;Stevanovic, Irena;Green, Andrew J.;Stracker, Travis H.;Lindsay, Howard D.;Doherty, Aidan J.
通讯作者：
Doherty, Aidan J.
影响因子：
14.9
作者：
Jordan, M;Schallhorn, A;Wurm, FM
通讯作者：
Wurm, FM
DOI：
10.1038/nrm.2017.53
发表时间：
2017-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Ray Chaudhuri A;Nussenzweig A
通讯作者：
Nussenzweig A