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Mol Cell. 2014 Dec 18;56(6):777-85. doi: 10.1016/j.molcel.2014.10.020. Epub 2014 Nov 26.

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

Author information

1
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Centro Andaluz de Biología Molecular y Medicina Regenerativa CABIMER, Universidad de Sevilla, Avenida Américo Vespucio, 41092 Seville, Spain.
3
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: cimprich@stanford.edu.

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.

PMID:
25435140
PMCID:
PMC4272638
DOI:
10.1016/j.molcel.2014.10.020
[Indexed for MEDLINE]
Free PMC Article

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