Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase

Steffi Herold (), Jacqueline Kalb, Gabriele Büchel, Carsten P. Ade, Apoorva Baluapuri, Jiajia Xu, Jan Koster, Daniel Solvie, Anne Carstensen, Christina Klotz, Sabrina Rodewald, Christina Schülein-Völk, Matthias Dobbelstein, Elmar Wolf, Jan Molenaar, Rogier Versteeg, Susanne Walz and Martin Eilers ()
Additional contact information
Steffi Herold: Biocenter, University of Würzburg
Jacqueline Kalb: Biocenter, University of Würzburg
Gabriele Büchel: Biocenter, University of Würzburg
Carsten P. Ade: Biocenter, University of Würzburg
Apoorva Baluapuri: Biocenter, University of Würzburg
Jiajia Xu: Biocenter, University of Würzburg
Jan Koster: Academic Medical Center (AMC), University of Amsterdam
Daniel Solvie: Biocenter, University of Würzburg
Anne Carstensen: Biocenter, University of Würzburg
Christina Klotz: Biocenter, University of Würzburg
Sabrina Rodewald: University of Göttingen
Christina Schülein-Völk: Biocenter, University of Würzburg
Matthias Dobbelstein: University of Göttingen
Elmar Wolf: Biocenter, University of Würzburg
Jan Molenaar: Department of Translational Research, Prinses Máxima Centrum voor Kinderoncologie
Rogier Versteeg: Academic Medical Center (AMC), University of Amsterdam
Susanne Walz: University of Würzburg
Martin Eilers: Biocenter, University of Würzburg

Nature, 2019, vol. 567, issue 7749, 545-549

Abstract: Abstract MYC is an oncogenic transcription factor that binds globally to active promoters and promotes transcriptional elongation by RNA polymerase II (RNAPII)1,2. Deregulated expression of the paralogous protein MYCN drives the development of neuronal and neuroendocrine tumours and is often associated with a particularly poor prognosis3. Here we show that, similar to MYC, activation of MYCN in human neuroblastoma cells induces escape of RNAPII from promoters. If the release of RNAPII from transcriptional pause sites (pause release) fails, MYCN recruits BRCA1 to promoter-proximal regions. Recruitment of BRCA1 prevents MYCN-dependent accumulation of stalled RNAPII and enhances transcriptional activation by MYCN. Mechanistically, BRCA1 stabilizes mRNA decapping complexes and enables MYCN to suppress R-loop formation in promoter-proximal regions. Recruitment of BRCA1 requires the ubiquitin-specific protease USP11, which binds specifically to MYCN when MYCN is dephosphorylated at Thr58. USP11, BRCA1 and MYCN stabilize each other on chromatin, preventing proteasomal turnover of MYCN. Because BRCA1 is highly expressed in neuronal progenitor cells during early development4 and MYC is less efficient than MYCN in recruiting BRCA1, our findings indicate that a cell-lineage-specific stress response enables MYCN-driven tumours to cope with deregulated RNAPII function.

Date: 2019
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DOI: 10.1038/s41586-019-1030-9

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