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BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair

2015; Elsevier BV; Volume: 57; Issue: 4 Linguagem: Inglês

10.1016/j.molcel.2015.01.011

1097-4164

Elodie Hatchi, Konstantina Skourti-Stathaki, Steffen Ventz, Luca Pinello, Angela Yen, Kinga Kamieniarz-Gdula, Stoil D. Dimitrov, Shailja Pathania, Kristine McKinney, Matthew L. Eaton, Manolis Kellis, Sarah J. Hill, Giovanni Parmigiani, Nicholas Proudfoot, David M. Livingston,

Genomics and Chromatin Dynamics

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.