BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation.
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Shivji, M., Renaudin, X., Williams, C., & Venkitaraman, A. (2018). BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation.. Cell Reports, 22 (4), 1031-1039. https://doi.org/10.1016/j.celrep.2017.12.086
The controlled release of RNA polymerase II (RNAPII) from promoter-proximal pausing (PPP) sites is critical for transcription elongation in metazoans. We show that the human tumor suppressor BRCA2 interacts with RNAPII to regulate PPP release, thereby preventing unscheduled RNA-DNA hybrids (R-loops) implicated in genomic instability and carcinogenesis. BRCA2 inactivation by depletion or cancer-causing mutations instigates RNAPII accumulation and R-loop accrual at PPP sites in actively transcribed genes, accompanied by γH2AX formation marking DNA breakage, which is reduced by ERCC4 endonuclease depletion. BRCA2 inactivation decreases RNAPII-associated factor 1 (PAF1) recruitment (which normally promotes RNAPII release) and diminishes H2B Lys120 ubiquitination, impeding nascent RNA synthesis. PAF1 depletion phenocopies, while its overexpression ameliorates, R-loop accumulation after BRCA2 inactivation. Thus, an unrecognized role for BRCA2 in the transition from promoter-proximal pausing to productive elongation via augmented PAF1 recruitment to RNAPII is subverted by disease-causing mutations, provoking R-loop-mediated DNA breakage in BRCA2-deficient cells.
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External DOI: https://doi.org/10.1016/j.celrep.2017.12.086
This record's URL: https://www.repository.cam.ac.uk/handle/1810/277398
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/