BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair
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Kellis_BRCA1.pdf
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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
Date Issued
February 2015
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
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.
MIT Department
Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.1016/j.molcel.2015.01.011
