Hatchi, ElodieSkourti-Stathaki, KonstantinaVentz, SteffenPinello, LucaYen, AngelaKamieniarz-Gdula, KingaDimitrov, StoilPathania, ShailjaMcKinney, Kristine M.Eaton, Matthew L.Kellis, ManolisHill, Sarah J.Parmigiani, GiovanniProudfoot, Nicholas J.Livingston, David M.2016-01-042015Hatchi, 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.2015.01.011.1097-2765http://nrs.harvard.edu/urn-3:HUL.InstRepos:23993645Summary 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.en-USJournal Article2016-01-0410.1016/j.molcel.2015.01.011