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

机译：BRCA1的招募限制了无停滞RNA聚合酶的Mycn驱动的积累

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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 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.
机译：Myc是一种致癌转录因子，其全球与活性启动子结合，并通过RNA聚合酶II（RNAPII）（1,2）促进转录伸长率。寄生蛋白质MYCN的Deroigation表达驱使神经元和神经内分泌肿瘤的发育，通常与预后特别差（3）相关。在这里，我们表明，类似于Myc，在人神经母细胞瘤细胞中的激活Mycn诱导来自启动子的RNAPII逃逸。如果从转录暂停站点（暂停发布）失败的RNAPII释放，MyCN会授予BRCA1到推动者 - 近端区域。 BRCA1的招聘可防止无停滞的RNAPII积累，并通过MYCN提高转录激活。机械地，BRCA1稳定mRNA拆下复合物，使MyCN能够在启动子 - 近端区域中抑制R环形成。 BRCA1的募集需要泛素特异性蛋白酶USP11，当MyCN在Thr58在Thr58下磷酸化时，特异性地结合mycn。 USP11，BRCA1和MyCN在染色质上均稳定，防止Mycn的蛋白酶体转换。由于BRCA1在早期发育期间在神经元祖细胞中高度表达（4）（4）并且Myc比招聘BRCA1中的MyCN效率低于Mycn，因此我们的研究结果表明，细胞谱系特异性应力反应使得Mycn驱动的肿瘤能够应对Dereculated RNAPII功能。

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  • 来源
    《Nature》 |2019年第7749期|545-549|共5页
  • 作者

    Herold Steffi; Kalb Jacqueline; Buechel Gabriele; Ade Carsten P.; Baluapuri Apoorva; Xu Jiajia; Koster Jan; Solvie Daniel; Carstensen Anne; Klotz Christina; Rodewald Sabrina; Schuelein-Voelk Christina; Dobbelstein Matthias; Wolf Elmar; Molenaar Jan; Versteeg Rogier; Walz Susanne; Eilers Martin;

  • 作者单位

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Canc Syst Biol Grp Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Amsterdam Dept Oncogen AMC Amsterdam Netherlands;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Gottingen Inst Mol Oncol Gottingen Ctr Mol Biosci Gottingen Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Univ Gottingen Inst Mol Oncol Gottingen Ctr Mol Biosci Gottingen Germany;

    Univ Wurzburg Canc Syst Biol Grp Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

    Prinses Maxima Ctr Kinderoncol Dept Translat Res Utrecht Netherlands;

    Univ Amsterdam Dept Oncogen AMC Amsterdam Netherlands;

    Univ Wurzburg Comprehens Canc Ctr Mainfranken Core Unit Bioinformat Bioctr Wurzburg Germany;

    Univ Wurzburg Theodor Boveri Inst Dept Biochem & Mol Biol Bioctr Wurzburg Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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