MYC promotes global transcription in part by controlling P-TEFb complex formation via DNA-binding independent inhibition of CDK9 SUMOylation  

作　　者：Qingqing Guan Zhaosu Chen Fang Yu Lingling Liu Yuanyong Huang Gang Wei Cheng-Ming Chiang Jiemin Wong Jiwen Li 

机构地区：[1]Shanghai Key Laboratory of Regulatory Biology,Fengxian District Central Hospital-ECNU Joint Center of Translational Medicine,Institute of Biomedical Sciences and School of Life Sciences,East China Normal University,Shanghai 200241,China [2]Department of Medicine,UF Health Cancer Center,University of Florida,Gainesville,FL 32610,USA [3]CAS Key Laboratory of Computational Biology,Shanghai Institute of Nutrition and Health,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China [4]Simmons Comprehensive Cancer Center,Department of Pharmacology,and Department of Biochemistry,University of Texas Southwestern Medical Center,Dallas TX 75390,USA

出　　处：《Science China(Life Sciences)》2023年第9期2167-2184,共18页中国科学（生命科学英文版）

基　　金：supported by the National Natural Science Foundation of China (32070643, 32130051, 31961133009);Science and Technology Commission of Shanghai Municipality (20JC1411500);the ECNU Public Platform for Innovation (011);the Instruments Sharing Platform of the School of Life Sciences,East China Normal University;supported by the US National Institutes of Health (NIH) grant 1RO1CA251698-01;Cancer Prevention and Research Institute of Texas (CPRIT) grant RP190077。

摘　　要：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 Cterminal 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.

关 键 词：MYC global transcription P-TEFB CDK9 SUMOYLATION cell transformation 

分 类 号：Q75[生物学—分子生物学]