title: Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II.
abstract: The association of DSIF and NELF with initiated RNA Polymerase II (Pol II) is the general mechanism for inducing promoter-proximal pausing of Pol II. However, it remains largely unclear how the paused Pol II is released in response to stimulation. Here, we show that the release of the paused Pol II is cooperatively regulated by multiple P-TEFbs which are recruited by bromodomain-containing protein Brd4 and super elongation complex (SEC) via different recruitment mechanisms. Upon stimulation, Brd4 recruits P-TEFb to Spt5/DSIF via a recruitment pathway consisting of Med1, Med23 and Tat-SF1, whereas SEC recruits P-TEFb to NELF-A and NELF-E via Paf1c and Med26, respectively. P-TEFb-mediated phosphorylation of Spt5, NELF-A and NELF-E results in the dissociation of NELF from Pol II, thereby transiting transcription from pausing to elongation. Additionally, we demonstrate that P-TEFb-mediated Ser2 phosphorylation of Pol II is dispensable for pause release. Therefore, our studies reveal a co-regulatory mechanism of Brd4 and SEC in modulating the transcriptional pause release by recruiting multiple P-TEFbs via a Mediator- and Paf1c-coordinated recruitment network.
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Xinxing
authors.initials: X
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: You
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Min
authors.identifier: 0000-0001-5183-1187
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Muhua
authors.initials: M
authors.lastname: Rao
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Yanheng
authors.initials: Y
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
authors.forename: Songkuan
authors.initials: S
authors.lastname: Zhuang
authors.affiliation: Department of Biochemistry, College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA lfchen@life.illinois.edu.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China liurz@xmu.edu.cn.
authors.forename: Runzhong
authors.initials: R
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China chenrc@xmu.edu.cn.
authors.forename: Ruichuan
authors.initials: R
authors.lastname: Chen
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D018797:Cell Cycle Proteins; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D042925:Positive Transcriptional Elongation Factor B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D061805:Transcription Elongation, Genetic / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D035602:Transcriptional Elongation Factors / Q000378:metabolism; D000092468:Bromodomain Containing Proteins
chemical_list: D000081:Acetamides; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D042925:Positive Transcriptional Elongation Factor B; D012319:RNA Polymerase II; D034741:RNA, Small Interfering; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C411985:NSMF protein, human; C112224:SUPT5H protein, human; C014026:hexamethylene bisacetamide