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PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts

Author

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  • Ann Liza Piberger

    (College of Medical and Dental Sciences, University of Birmingham)

  • Akhil Bowry

    (College of Medical and Dental Sciences, University of Birmingham)

  • Richard D. W. Kelly

    (College of Medical and Dental Sciences, University of Birmingham)

  • Alexandra K. Walker

    (College of Medical and Dental Sciences, University of Birmingham)

  • Daniel González-Acosta

    (Spanish National Cancer Research Centre)

  • Laura J. Bailey

    (University of Sussex, Falmer)

  • Aidan J. Doherty

    (University of Sussex, Falmer)

  • Juan Méndez

    (Spanish National Cancer Research Centre)

  • Joanna R. Morris

    (College of Medical and Dental Sciences, University of Birmingham)

  • Helen E. Bryant

    (University of Sheffield)

  • Eva Petermann

    (College of Medical and Dental Sciences, University of Birmingham)

Abstract

Stalled replication forks can be restarted and repaired by RAD51-mediated homologous recombination (HR), but HR can also perform post-replicative repair after bypass of the obstacle. Bulky DNA adducts are important replication-blocking lesions, but it is unknown whether they activate HR at stalled forks or behind ongoing forks. Using mainly BPDE-DNA adducts as model lesions, we show that HR induced by bulky adducts in mammalian cells predominantly occurs at post-replicative gaps formed by the DNA/RNA primase PrimPol. RAD51 recruitment under these conditions does not result from fork stalling, but rather occurs at gaps formed by PrimPol re-priming and resection by MRE11 and EXO1. In contrast, RAD51 loading at double-strand breaks does not require PrimPol. At bulky adducts, PrimPol promotes sister chromatid exchange and genetic recombination. Our data support that HR at bulky adducts in mammalian cells involves post-replicative gap repair and define a role for PrimPol in HR-mediated DNA damage tolerance.

Suggested Citation

  • Ann Liza Piberger & Akhil Bowry & Richard D. W. Kelly & Alexandra K. Walker & Daniel González-Acosta & Laura J. Bailey & Aidan J. Doherty & Juan Méndez & Joanna R. Morris & Helen E. Bryant & Eva Peter, 2020. "PrimPol-dependent single-stranded gap formation mediates homologous recombination at bulky DNA adducts," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-19570-7
    DOI: 10.1038/s41467-020-19570-7
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    Cited by:

    1. Jude B. Khatib & Ashna Dhoonmoon & George-Lucian Moldovan & Claudia M. Nicolae, 2024. "PARP10 promotes the repair of nascent strand DNA gaps through RAD18 mediated translesion synthesis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Zuzana Machacova & Katarina Chroma & David Lukac & Iva Protivankova & Pavel Moudry, 2024. "DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    4. Tanay Thakar & Ashna Dhoonmoon & Joshua Straka & Emily M. Schleicher & Claudia M. Nicolae & George-Lucian Moldovan, 2022. "Lagging strand gap suppression connects BRCA-mediated fork protection to nucleosome assembly through PCNA-dependent CAF-1 recycling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Maria Dilia Palumbieri & Chiara Merigliano & Daniel González-Acosta & Danina Kuster & Jana Krietsch & Henriette Stoy & Thomas Känel & Svenja Ulferts & Bettina Welter & Joël Frey & Cyril Doerdelmann & , 2023. "Nuclear actin polymerization rapidly mediates replication fork remodeling upon stress by limiting PrimPol activity," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Domagoj Vugic & Isaac Dumoulin & Charlotte Martin & Anna Minello & Lucia Alvaro-Aranda & Jesus Gomez-Escudero & Rady Chaaban & Rana Lebdy & Catharina Nicolai & Virginie Boucherit & Cyril Ribeyre & Ang, 2023. "Replication gap suppression depends on the double-strand DNA binding activity of BRCA2," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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