期刊
MOLECULAR CELL
卷 57, 期 4, 页码 636-647出版社
CELL PRESS
DOI: 10.1016/j.molcel.2015.01.011
关键词
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资金
- National Cancer Institute (NCI) - Mechanisms of Breast Development and Carcinogenesis [2PO1CA80111-16]
- BRCA1 Function in Post Damage Foci [5R01CA136512-05]
- Marie Curie IEF
- Wellcome Trust
- NCI [5P30 CA006516-46]
- Direct For Biological Sciences
- Div Of Biological Infrastructure [0644282] Funding Source: National Science Foundation
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 gamma-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.
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