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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, View ORCID ProfileNicholas D. Lakin
doi: https://doi.org/10.1101/243071
George E. Ronson
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK
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Ann Liza Piberger
2Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Martin R. Higgs
2Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Anna L. Olsen
3Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
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Grant S. Stewart
2Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Peter J. McHugh
3Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK
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Eva Petermann
2Institute of Cancer and Genomic Sciences, University of Birmingham, Edgbaston, Birmingham, UK
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Nicholas D. Lakin
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK
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  • ORCID record for Nicholas D. Lakin
  • For correspondence: nicholas.lakin@bioch.ox.ac.uk
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Abstract

PARP1 regulates the repair of DNA single strand breaks (SSBs) 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. Whilst 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 due 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 through stabilising replication forks that encounter BER intermediates.

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Posted January 04, 2018.
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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, Nicholas D. Lakin
bioRxiv 243071; doi: https://doi.org/10.1101/243071
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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, Nicholas D. Lakin
bioRxiv 243071; doi: https://doi.org/10.1101/243071

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