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Cited by 478

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

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Hatchi, Elodie, Skourti-Stathaki, Konstantina, Ventz, Steffen, Pinello, Luca, Yen, Angela, Kamieniarz-Gdula, Kinga, Dimitrov, Stoil, Pathania, Shailja, McKinney, Kristine M., Eaton, Matthew L., Kellis, Manolis, Hill, Sarah J., Parmigiani, Giovanni, Proudfoot, Nicholas J., Livingston, David M.·2015·Molecular Cell
DOI 10.1016/j.molcel.2015.01.011
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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.

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Metadata

Authors
Hatchi, E., Skourti-Stathaki, K., Ventz, S., Pinello, L., Yen, A., Kamieniarz-Gdula, K., Dimitrov, S., Pathania, S., McKinney, K. M., Eaton, M. L., Kellis, M., Hill, S. J., Parmigiani, G., Proudfoot, N. J., & Livingston, D. M.
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2015-02
Volume
57
Issue
4
Pages
636-647
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2015.01.011
OpenAlex
W2103694115
Cited by
478
References
13
FWCI
15.05
Type
journal article
Language
en
Open access
hybrid
Licence

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CoChat. (2026). Citation check: BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair. https://app.cochat.ai/papers/10.1016/j.molcel.2015.01.011
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Hatchi, E., Skourti-Stathaki, K., Ventz, S., Pinello, L., Yen, A., Kamieniarz-Gdula, K., Dimitrov, S., Pathania, S., McKinney, K. M., Eaton, M. L., Kellis, M., Hill, S. J., Parmigiani, G., Proudfoot, N. J., & Livingston, D. M. (2015). BRCA1 Recruitment to Transcriptional Pause Sites Is Required for R-Loop-Driven DNA Damage Repair. Molecular Cell. https://doi.org/10.1016/j.molcel.2015.01.011

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