BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair
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Author
Skourti-Stathaki, Konstantina
Yen, Angela
Kamieniarz-Gdula, Kinga
McKinney, Kristine M.
Eaton, Matthew L.
Kellis, Manolis
Hill, Sarah J.
Proudfoot, Nicholas J.
Livingston, David M.
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1016/j.molcel.2015.01.011Metadata
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Hatchi, E., K. Skourti-Stathaki, S. Ventz, L. Pinello, A. Yen, K. Kamieniarz-Gdula, S. Dimitrov, et al. 2015. “BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair.” Molecular Cell 57 (4): 636-647. doi:10.1016/j.molcel.2015.01.011. http://dx.doi.org/10.1016/j.molcel.2015.01.011.Abstract
Summary 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4351672/pdf/Terms of Use
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