PARP1 and PARP2 stabilise replication forks at base excision repair intermediates through Fbh1-dependent Rad51 regulation

George E. Ronson, Ann Liza Piberger, Martin R. Higgs, Anna L. Olsen, Grant S. Stewart, Peter J. McHugh, Eva Petermann and Nicholas D. Lakin ()
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George E. Ronson: University of Oxford
Ann Liza Piberger: University of Birmingham
Martin R. Higgs: University of Birmingham
Anna L. Olsen: University of Oxford
Grant S. Stewart: University of Birmingham
Peter J. McHugh: University of Oxford
Eva Petermann: University of Birmingham
Nicholas D. Lakin: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-03159-2

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