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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Podrobná bibliografie
Vydáno v:	Molecular cell Ročník 56; číslo 6; s. 777
Hlavní autoři:	Sollier, Julie, Stork, Caroline Townsend, García-Rubio, María L, Paulsen, Renee D, Aguilera, Andrés, Cimprich, Karlene A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 18.12.2014
Témata:	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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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4164 1097-4164
DOI:	10.1016/j.molcel.2014.10.020