BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair.

Mol Cell
Authors
Keywords
Abstract

The mechanisms contributing to transcription-associated genomic instability are both complex and incompletely understood. Although R-loops are normal transcriptional intermediates, they are also associated with genomic instability. Here, we show that BRCA1 is recruited to R-loops that form normally over a subset of transcription termination regions. There it mediates the recruitment of a specific, physiological binding partner, senataxin (SETX). Disruption of this complex led to R-loop-driven DNA damage at those loci as reflected by adjacent γ-H2AX accumulation and ssDNA breaks within the untranscribed strand of relevant R-loop structures. Genome-wide analysis revealed widespread BRCA1 binding enrichment at R-loop-rich termination regions (TRs) of actively transcribed genes. Strikingly, within some of these genes in BRCA1 null breast tumors, there are specific insertion/deletion mutations located close to R-loop-mediated BRCA1 binding sites within TRs. Thus, BRCA1/SETX complexes support a DNA repair mechanism that addresses R-loop-based DNA damage at transcriptional pause sites.

Year of Publication
2015
Journal
Mol Cell
Volume
57
Issue
4
Pages
636-47
Date Published
2015 Feb 19
ISSN
1097-4164
URL
DOI
10.1016/j.molcel.2015.01.011
PubMed ID
25699710
PubMed Central ID
PMC4351672
Links
Grant list
R01 HG004037 / HG / NHGRI NIH HHS / United States
2P01CA80111-16 / CA / NCI NIH HHS / United States
P01 CA080111 / CA / NCI NIH HHS / United States
R01 CA136512 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
5P30 CA006516-46 / CA / NCI NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States
Wellcome Trust / United Kingdom
5R01CA136512-05 / CA / NCI NIH HHS / United States