BRCA1 recruitment to transcriptional pause sites is required for R-loop-driven DNA damage repair

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)636-647
Number of pages12
JournalMolecular Cell
Volume57
Issue number4
DOIs
StatePublished - Feb 19 2015
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

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, 57(4), 636-647. https://doi.org/10.1016/j.molcel.2015.01.011