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

Author(s)
Hatchi, Elodie; Skourti-Stathaki, Konstantina; Ventz, Steffen; Pinello, Luca; Yen, Angela; Kamieniarz-Gdula, Kinga; Dimitrov, Stoil; Pathania, Shailja; McKinney, Kristine M.; Kellis, Manolis; Hill, Sarah J.; Parmigiani, Giovanni; Proudfoot, Nicholas J.; Livingston, David M.; Eaton, Matthew Lucas; ... Show more Show less
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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.
Date issued
2015-02
URI
http://hdl.handle.net/1721.1/100779
Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory; Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
Journal
Molecular Cell
Publisher
Elsevier
Citation
Hatchi, Elodie, Konstantina Skourti-Stathaki, Steffen Ventz, Luca Pinello, Angela Yen, Kinga Kamieniarz-Gdula, Stoil Dimitrov, et al. “BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair.” Molecular Cell 57, no. 4 (February 2015): 636–647.
Version: Final published version
ISSN
10972765
1097-4164

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