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Molecular basis for PrimPol recruitment to replication forks by RPA

Author

Listed:
  • Thomas A. Guilliam

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

  • Nigel C. Brissett

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

  • Aaron Ehlinger

    (Vanderbilt University School of Medicine)

  • Benjamin A. Keen

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

  • Peter Kolesar

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

  • Elaine M. Taylor

    (Lancaster Medical School, Faculty of Health and Medicine, Lancaster University)

  • Laura J. Bailey

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

  • Howard D. Lindsay

    (Lancaster Medical School, Faculty of Health and Medicine, Lancaster University)

  • Walter J. Chazin

    (Vanderbilt University School of Medicine)

  • Aidan J. Doherty

    (Genome Damage and Stability Centre, School of Life Sciences, University of Sussex)

Abstract

DNA damage and secondary structures can stall the replication machinery. Cells possess numerous tolerance mechanisms to complete genome duplication in the presence of such impediments. In addition to translesion synthesis (TLS) polymerases, most eukaryotic cells contain a multifunctional replicative enzyme called primase–polymerase (PrimPol) that is capable of directly bypassing DNA damage by TLS, as well as repriming replication downstream of impediments. Here, we report that PrimPol is recruited to reprime through its interaction with RPA. Using biophysical and crystallographic approaches, we identify that PrimPol possesses two RPA-binding motifs and ascertained the key residues required for these interactions. We demonstrate that one of these motifs is critical for PrimPol’s recruitment to stalled replication forks in vivo. In addition, biochemical analysis reveals that RPA serves to stimulate the primase activity of PrimPol. Together, these findings provide significant molecular insights into PrimPol’s mode of recruitment to stalled forks to facilitate repriming and restart.

Suggested Citation

  • Thomas A. Guilliam & Nigel C. Brissett & Aaron Ehlinger & Benjamin A. Keen & Peter Kolesar & Elaine M. Taylor & Laura J. Bailey & Howard D. Lindsay & Walter J. Chazin & Aidan J. Doherty, 2017. "Molecular basis for PrimPol recruitment to replication forks by RPA," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15222
    DOI: 10.1038/ncomms15222
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    Cited by:

    1. Sahiti Kuppa & Jaigeeth Deveryshetty & Rahul Chadda & Jenna R. Mattice & Nilisha Pokhrel & Vikas Kaushik & Angela Patterson & Nalini Dhingra & Sushil Pangeni & Marisa K. Sadauskas & Sajad Shiekh & Ham, 2022. "Rtt105 regulates RPA function by configurationally stapling the flexible domains," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. 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.
    3. Zhihua Kang & Pan Fu & Allen L. Alcivar & Haiqing Fu & Christophe Redon & Tzeh Keong Foo & Yamei Zuo & Caiyong Ye & Ryan Baxley & Advaitha Madireddy & Remi Buisson & Anja-Katrin Bielinsky & Lee Zou & , 2021. "BRCA2 associates with MCM10 to suppress PRIMPOL-mediated repriming and single-stranded gap formation after DNA damage," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

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