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

Nature Communications
Ann Liza PibergerEva Petermann

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.

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Citations

Jan 31, 2021·Molecular Cell·Annabel QuinetAlessandro Vindigni
Mar 22, 2021·Nucleic Acids Research·Lewis J BainbridgeAidan J Doherty
May 13, 2021·Nucleic Acids Research·Tanay Thakar, George-Lucian Moldovan
May 31, 2021·Trends in Cancer·Akhil BowryEva Petermann
Jun 16, 2021·The EMBO Journal·Daniel González-AcostaJuan Méndez
Aug 30, 2021·Current Opinion in Genetics & Development·Yea-Lih Lin, Philippe Pasero
Sep 4, 2021·Scientific Reports·Elizaveta O BoldinovaAlena V Makarova

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Methods Mentioned

BETA
electrophoresis
flow cytometry
DNA fiber
FCS
scraping

Software Mentioned

SMART
Excel
BD FacsDiva
Graphpad Prism
ImageJ
Volocity
PrimPol

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