Phosphorylated MED1 links transcription recycling and cancer growth.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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, Q

Published Date

  • May 6, 2022

Published In

Volume / Issue

  • 50 / 8

Start / End Page

  • 4450 - 4463

PubMed ID

  • 35394046

Pubmed Central ID

  • PMC9071494

Electronic International Standard Serial Number (EISSN)

  • 1362-4962

Digital Object Identifier (DOI)

  • 10.1093/nar/gkac246

Language

  • eng

Conference Location

  • England