Ronson George E, Piberger Ann Liza, Higgs Martin R, Olsen Anna L, Stewart Grant S, McHugh Peter J, Petermann Eva, Lakin Nicholas D
Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, B15 2TT, Birmingham, UK.
Nat Commun. 2018 Feb 21;9(1):746. doi: 10.1038/s41467-018-03159-2.
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可调节直接产生的或在碱基切除修复（BER）过程中产生的DNA单链断裂的修复。然而，PARP2在这些及其他修复机制中的作用尚不清楚。在此，我们报告了PARP2在稳定复制叉中的必要性，这些复制叉通过Fbh1依赖的Rad51调节来遇到BER中间体。虽然PARP2对于细胞耐受单链断裂或同源重组功能障碍并非必需，但它在BER中与PARP1功能冗余。因此，PARP1和PARP2的联合破坏会导致BER缺陷，由于无法在受损复制叉处稳定Rad51并防止不受控制的DNA切除，导致与复制相关的DNA损伤水平升高。总之，我们的结果表明PARP1和PARP2如何通过直接促进BER以及稳定遇到BER中间体的复制叉来调节DNA碱基损伤耐受的两个独立但内在相关的方面。
