Molecular basis for PrimPol recruitment to replication forks by RPA

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 and Aidan J. Doherty ()
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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

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms15222

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DOI: 10.1038/ncomms15222

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