MYCN Recruits BRCA1 to Limit Accumulation of Stalled RNA Polymerase

MYC is an oncogenic transcription factor that can promote transcriptional elongation by RNA polymerase II (RNAPII). Herold, Kalb, Büchel, and colleagues show that the neuronal and neuroendocrine lineage-specific paralog MYCN can similarly mediate escape of RNAPII from promoters and recruits BRCA1 to prevent RNAPII stalling at promoter-proximal regions. In neuroblastoma cells, activation of a MYCN–ER fusion protein via 4-hydroxytamoxifen treatment generated a MYCN-specific expression profile, with elongating RNAPII increased in the body of activated genes. A shRNA screen revealed that MYCN–ER activation led to increased dependence on BRCA1, suggesting that BRCA1 might control the transcriptional functions of MYCN. Genome-wide methylation data showed that the BRCA1 promoter was significantly hypomethylated in high-risk and MYCN-amplified neuroblastoma, and MYCN activation resulted in recruitment of BRCA1 to promoter-proximal regions of activated genes, overlapping closely with MYCN binding sites; the extent of BRCA1 recruitment correlated with expression of the downstream gene. MYCN activation increased the association of BRCA1 with promoter-proximal RNAPII, and blocking RNAPII elongation further increased this association. Depletion of BRCA1 resulted in accumulation of RNAPII at promoter-proximal regions following MYCN activation. Activation of MYCN also suppressed R-loop formation in a BRCA1-dependent manner, and BRCA1 depletion resulted in complete loss of the mRNA decapping enzyme DCP1A from promoter-proximal regions, indicating that recruitment of BRCA1 by MYCN enables mRNA decapping when RNAPII stalls. MYCN and BRCA1 did not directly interact, but formed a stable complex with the ubiquitin hydrolase USP11, which stabilized both MYCN and BRCA1 protein levels to maintain their recruitment to promoter-proximal regions. MYCN, but not MYC, promotes association of USP11 with BRCA1, and MYCN recruited BRCA1 to chromatin much more efficiently than MYC. Taken together, these results suggest that recruitment of BRCA1 by MYCN comprises a cell lineage–specific transcriptional stress response that enables MYCN-driven tumors to mitigate dysregulated RNAPII function.

Herold S, Kalb J, Büchel G, Ade CP, Baluapuri A, Xu J, et al. Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase. Nature 2019;567:545–9.

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