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

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, t...

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Published in:Molecular cell Vol. 56; no. 6; p. 777
Main Authors: Sollier, Julie, Stork, Caroline Townsend, García-Rubio, María L, Paulsen, Renee D, Aguilera, Andrés, Cimprich, Karlene A
Format: Journal Article
Language:English
Published: United States 18.12.2014
Subjects:
DNA Damage
DNA Repair
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Endonucleases - genetics
Endonucleases - metabolism
Genome, Human
Genomic Instability
HeLa Cells
Humans
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
RNA Replicase - genetics
RNA Replicase - metabolism
RNA, Fungal - genetics
RNA, Fungal - metabolism
Saccharomyces cerevisiae - genetics
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
ISSN:1097-4164, 1097-4164
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Summary: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.
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ISSN:1097-4164
1097-4164
DOI:10.1016/j.molcel.2014.10.020