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R-loop formation during S phase is restricted by PrimPol-mediated repriming

journal contribution
posted on 2023-06-09, 16:28 authored by Sasa S?vikovic´, Alastair Crisp, Sue Mei Tan-Wong, Thomas A Guilliam, Aidan DohertyAidan Doherty, Nicholas Proudfoot, Guillaume Guilbaud, Julian Sale
During DNA replication conflicts with ongoing transcription are frequent and require careful management to avoid genetic instability. R-loops, three stranded nucleic acid structures comprising a DNA:RNA hybrid and displaced single stranded DNA, are important drivers of damage arising from such conflicts. How R-loops stall replication and the mechanisms that restrain their formation during S phase are incompletely understood. Here we show in vivo how R-loop formation drives a short purine-rich repeat, (GAA)10, to become a replication impediment that engages the repriming activity of the primase-polymerase PrimPol. Further, the absence of PrimPol leads to significantly increased R-loop formation around this repeat during S phase. We extend this observation by showing that PrimPol suppresses R-loop formation in genes harbouring secondary structure-forming sequences, exemplified by G quadruplex and H-DNA motifs, across the genome in both avian and human cells. Thus, R- loops promote the creation of replication blocks at susceptible structure-forming sequences, while PrimPol-dependent repriming limits the extent of unscheduled R-loop formation at these sequences, mitigating their impact on replication.

Funding

Understanding the role of PrimPol in damage tolerance during genome replication in eukaryotic cells; G1621; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/M008800/1

The role of a novel family of eukaryotic DNA polymerases in mitochondrial DNA replication; G0207; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/H019723/1

History

Publication status

  • Published

File Version

  • Published version

Journal

The EMBO Journal

ISSN

0261-4189

Publisher

EMBO Press

Issue

3

Volume

38

Page range

1-19

Article number

e99793

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Research groups affiliated with

  • Genome Damage and Stability Centre Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-01-09

First Open Access (FOA) Date

2019-01-09

First Compliant Deposit (FCD) Date

2019-01-09

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