神经母细胞瘤
RNA聚合酶Ⅱ
生物
发起人
染色质
抄写(语言学)
细胞生物学
癌症研究
转录因子
基因
分子生物学
遗传学
基因表达
细胞培养
语言学
哲学
作者
Steffi Herold,Jacqueline Kalb,Gabriele Büchel,Carsten P. Ade,Apoorva Baluapuri,Jiajia Xu,Jan Köster,Daniel Solvie,Anne Carstensen,Christina Klotz,Sabrina Rodewald,Christina Schülein‐Völk,Matthias Dobbelstein,Elmar Wolf,Jan J. Molenaar,Rogier Versteeg,Susanne Walz,Martin Eilers
出处
期刊:Nature
[Springer Nature]
日期:2019-03-01
卷期号:567 (7749): 545-549
被引量:78
标识
DOI:10.1038/s41586-019-1030-9
摘要
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. In human neuroblastoma tumours, MYCN is engaged in a USP11–BRCA1-dependent manner to suppress the accumulation of stalled RNAPII and induces both the activation and repression of genes.
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