TY - JOUR
T1 - Recruitment of BRCA1 limits MYCN-driven accumulation of stalled RNA polymerase
AU - Herold, Steffi
AU - Kalb, Jacqueline
AU - Büchel, Gabriele
AU - Ade, Carsten P.
AU - Baluapuri, Apoorva
AU - Xu, Jiajia
AU - Koster, Jan
AU - Solvie, Daniel
AU - Carstensen, Anne
AU - Klotz, Christina
AU - Rodewald, Sabrina
AU - Schülein-Völk, Christina
AU - Dobbelstein, Matthias
AU - Wolf, Elmar
AU - Molenaar, Jan
AU - Versteeg, Rogier
AU - Walz, Susanne
AU - Eilers, Martin
PY - 2019/3
Y1 - 2019/3
N2 - 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 prognosis 3 . 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 development 4 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.
AB - 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 prognosis 3 . 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 development 4 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063257982&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30894746
U2 - https://doi.org/10.1038/s41586-019-1030-9
DO - https://doi.org/10.1038/s41586-019-1030-9
M3 - Comment/Letter to the editor
C2 - 30894746
SN - 0028-0836
VL - 567
SP - 545
EP - 549
JO - NATURE
JF - NATURE
IS - 7749
ER -