Transcription-coupled nucleotide excision repair factors promote R-loop-induced genome instability.

Abstract:

:R-loops, consisting of an RNA-DNA hybrid and displaced single-stranded DNA, are physiological structures that regulate various cellular processes occurring on chromatin. Intriguingly, changes in R-loop dynamics have also been associated with DNA damage accumulation and genome instability; however, the mechanisms underlying R-loop-induced DNA damage remain unknown. Here we demonstrate in human cells that R-loops induced by the absence of diverse RNA processing factors, including the RNA/DNA helicases Aquarius (AQR) and Senataxin (SETX), or by the inhibition of topoisomerase I, are actively processed into DNA double-strand breaks (DSBs) by the nucleotide excision repair endonucleases XPF and XPG. Surprisingly, DSB formation requires the transcription-coupled nucleotide excision repair (TC-NER) factor Cockayne syndrome group B (CSB), but not the global genome repair protein XPC. These findings reveal an unexpected and potentially deleterious role for TC-NER factors in driving R-loop-induced DNA damage and genome instability.

journal_name

Mol Cell

journal_title

Molecular cell

authors

Sollier J,Stork CT,García-Rubio ML,Paulsen RD,Aguilera A,Cimprich KA

doi

10.1016/j.molcel.2014.10.020

subject

Has Abstract

pub_date

2014-12-18 00:00:00

pages

777-85

issue

6

eissn

1097-2765

issn

1097-4164

pii

S1097-2765(14)00830-2

journal_volume

56

pub_type

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