PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation.
PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation.
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DOI：
10.1038/s41467-018-03159-2
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发表时间：
2018-02-21
影响因子：
16.6
通讯作者：
Lakin ND
中科院分区：
文献类型：
--
作者：
Ronson GE;Piberger AL;Higgs MR;Olsen AL;Stewart GS;McHugh PJ;Petermann E;Lakin ND
PARP1调控直接或在碱基切除修复（BER）过程中产生的DNA单链断裂的修复。然而，PARP2在这些和其他修复机制中的作用尚不清楚。在这里，我们报告了PARP2通过依赖于fbh1的Rad51调控来稳定遇到BER中间体的复制分叉。PARP2在细胞对SSBs的耐受或同源重组功能障碍中是不必要的，而PARP1在BER中是多余的。因此，PARP1和PARP2的联合破坏导致BER缺陷，由于无法稳定受损复制叉上的Rad51并防止失控的DNA切除，导致复制相关DNA损伤水平升高。总之，我们的研究结果证明了PARP1和PARP2如何通过直接促进BER和稳定遇到BER中间体的复制分叉来调节DNA碱基损伤耐受性的两个独立但内在联系的方面。PARP1在DNA断裂修复和碱基切除修复中具有明确的作用，而PARP2的作用则不太清楚。在这里，作者展示了PARP2在稳定遇到碱基切除修复中间体的复制分叉时的需求。
PARP1 regulates the repair of DNA single-strand breaks generated directly, or during base excision repair (BER). However, the role of PARP2 in these and other repair mechanisms is unknown. Here, we report a requirement for PARP2 in stabilising replication forks that encounter BER intermediates through Fbh1-dependent regulation of Rad51. Whereas PARP2 is dispensable for tolerance of cells to SSBs or homologous recombination dysfunction, it is redundant with PARP1 in BER. Therefore, combined disruption of PARP1 and PARP2 leads to defective BER, resulting in elevated levels of replication-associated DNA damage owing to an inability to stabilise Rad51 at damaged replication forks and prevent uncontrolled DNA resection. Together, our results demonstrate how PARP1 and PARP2 regulate two independent, but intrinsically linked aspects of DNA base damage tolerance by promoting BER directly, and by stabilising replication forks that encounter BER intermediates. PARP1 has a well characterised role in DNA break repair and base excision repair, whereas the role of PARP2 is less well understood. Here, the authors show a requirement for PARP2 in stabilising replication forks that encounter base excision repair intermediates.
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