BRCA2 Regulates Transcription Elongation by RNA Polymerase II to Prevent R-Loop Accumulation.

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Shivji, MKK 
Williams, CH 
Venkitaraman, AR 

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.

BRCA2, PAF1, R-loops, RNA polymerase II, genomic instability, transcription elongation, BRCA2 Protein, Humans, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Transcriptional Activation
Journal Title
Cell Reports
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Volume Title
MRC (unknown)
MRC (MR/N501876/1)
Medical Research Council (G1001521)
MRC (4050551988)
Medical Research Council (MC_UU_12022/1)
MRC (MC_UU_12022/8)