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

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 and Eva Petermann ()
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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

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19570-7

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