MYC promotes global transcription in part by controlling P-TEFb complex formation via DNA-binding independent inhibition of CDK9 SUMOylation.
MYC promotes global transcription in part by controlling P-TEFb complex formation via DNA-binding independent inhibition of CDK9 SUMOylation.
复制标题
DOI：
10.1007/s11427-022-2281-6
复制
发表时间：
2023-09
影响因子：
9.1
通讯作者：
Li, Jiwen
中科院分区：
文献类型：
--
作者：
Guan, Qingqing;Chen, Zhaosu;Yu, Fang;Liu, Lingling;Huang, Yuanyong;Wei, Gang;Chiang, Cheng-Ming;Wong, Jiemin;Li, Jiwen
MYC是一种致癌转录因子，在过度表达时在增强全局转录中起着新的作用。然而，MYC如何促进全局转录仍然存在争议。在这里，我们使用了一系列MYC突变体来剖析MYC驱动的全局转录的分子基础。我们发现，缺乏DNA结合或已知转录激活活性的MYC突变体仍然可以促进全局转录并增强RNA聚合酶（Pol） II c端结构域（CTD）的丝氨酸2磷酸化（Ser2P），这是活性延长RNA Pol II的标志。MYC中的两个不同区域可以促进Pol II CTD的全局转录和Ser2P。各种MYC突变体促进全局转录和Ser2P的能力与其抑制CDK9 SUMOylation和增强正转录延伸因子b （P-TEFb）复合物形成的能力相关。我们发现MYC通过抑制CDK9和SUMO酶（包括UBC9和PIAS1）之间的相互作用来抑制CDK9的SUMO化。此外，MYC增强全局转录的活性对其促进细胞增殖和转化的活性有积极的作用。总之，我们的研究表明，MYC通过序列特异性dna结合活性独立的方式促进活性P-TEFb复合物的形成，至少在一定程度上促进了全局转录。
MYC is an oncogenic transcription factor with a novel role in enhancing global transcription when overexpressed. However, how MYC promotes global transcription remains controversial. Here, we used a series of MYC mutants to dissect the molecular basis for MYC-driven global transcription. We found that MYC mutants deficient in DNA binding or known transcriptional activation activities can still promote global transcription and enhance serine 2 phosphorylation (Ser2P) of the RNA polymerase (Pol) II C-terminal domain (CTD), a hallmark of active elongating RNA Pol II. Two distinct regions within MYC can promote global transcription and Ser2P of Pol II CTD. The ability of various MYC mutants to promote global transcription and Ser2P correlates with their ability to suppress CDK9 SUMOylation and enhance positive transcription elongation factor b (P-TEFb) complex formation. We showed that MYC suppresses CDK9 SUMOylation by inhibiting the interaction between CDK9 and SUMO enzymes including UBC9 and PIAS1. Furthermore, MYC’s activity in enhancing global transcription positively contributes to its activity in promoting cell proliferation and transformation. Together, our study demonstrates that MYC promotes global transcription, at least in part, by promoting the formation of the active P-TEFb complex via a sequence-specific DNA-binding activity-independent manner.
登录
查看更多内容
DOI：
10.1038/s41580-020-0215-2
发表时间：
2020-05
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Baluapuri A;Wolf E;Eilers M
通讯作者：
Eilers M
影响因子：
4.3
作者：
Gargano, Barbara;Amente, Stefano;Lania, Luigi
通讯作者：
Lania, Luigi
影响因子：
8
作者：
Cowling, V. H.;Cole, M. D.
通讯作者：
Cole, M. D.
影响因子：
5.3
作者：
Faiola, F;Liu, XH;Martinez, E
通讯作者：
Martinez, E
影响因子：
16
作者：
Kalkat, Manpreet;Resetca, Diana;Penn, Linda Z.
通讯作者：
Penn, Linda Z.