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Mol Cell. 2015 Feb 19;57(4):636-647. doi: 10.1016/j.molcel.2015.01.011.

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

Author information

1
Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: elodiey_hatchi@dfci.harvard.edu.
2
Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, UK.
3
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Computer Science and Artificial Intelligence Laboratory (CSAIL), MIT, Cambridge, MA 02139, USA.
5
Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
6
Department of Genetics, Harvard Medical School, Boston, MA 02215, USA; Department of Cancer Biology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA. Electronic address: david_livingston@dfci.harvard.edu.

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.

PMID:
25699710
PMCID:
PMC4351672
DOI:
10.1016/j.molcel.2015.01.011
[Indexed for MEDLINE]
Free PMC Article

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