Phosphorylated MED1 links transcription recycling and cancer growth. Nucleic Acids Res 2022 May 06;50(8):4450-4463
Date
04/09/2022Pubmed ID
35394046Pubmed Central ID
PMC9071494DOI
10.1093/nar/gkac246Scopus ID
2-s2.0-85129998167 (requires institutional sign-in at Scopus site) 3 CitationsAbstract
Mediator activates RNA polymerase II (Pol II) function during transcription, but it remains unclear whether Mediator is able to travel with Pol II and regulate Pol II transcription beyond the initiation and early elongation steps. By using in vitro and in vivo transcription recycling assays, we find that human Mediator 1 (MED1), when phosphorylated at the mammal-specific threonine 1032 by cyclin-dependent kinase 9 (CDK9), dynamically moves along with Pol II throughout the transcribed genes to drive Pol II recycling after the initial round of transcription. Mechanistically, MED31 mediates the recycling of phosphorylated MED1 and Pol II, enhancing mRNA output during the transcription recycling process. Importantly, MED1 phosphorylation increases during prostate cancer progression to the lethal phase, and pharmacological inhibition of CDK9 decreases prostate tumor growth by decreasing MED1 phosphorylation and Pol II recycling. Our results reveal a novel role of MED1 in Pol II transcription and identify phosphorylated MED1 as a targetable driver of dysregulated Pol II recycling in cancer.
Author List
Chen Z, Ye Z, Soccio RE, Nakadai T, Hankey W, Zhao Y, Huang F, Yuan F, Wang H, Cui Z, Sunkel B, Wu D, Dzeng RK, Thomas-Ahner JM, Huang THM, Clinton SK, Huang J, Lazar MA, Jin VX, Roeder RG, Wang QAuthor
Victor X. Jin PhD Professor in the Institute for Health and Equity department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsHumans
Male
Mammals
Mediator Complex
Mediator Complex Subunit 1
Neoplasms
Phosphorylation
RNA Polymerase II
Transcription, Genetic
