Phosphorylated MED1 links transcription recycling and cancer growth

Zhong Chen; Zhenqing Ye; Raymond E. Soccio; Tomoyoshi Nakadai; William Hankey; Yue Zhao; Furong Huang; Fuwen Yuan; Hongyan Wang; Zhifen Cui; Benjamin Sunkel; Dayong Wu; Richard K. Dzeng; Jennifer M. Thomas-Ahner; Tim H.M. Huang; Steven K. Clinton; Jiaoti Huang; Mitchell A. Lazar; Victor X. Jin; Robert G. Roeder; Qianben Wang

doi:10.1093/nar/gkac246

Phosphorylated MED1 links transcription recycling and cancer growth

Zhong Chen, Zhenqing Ye, Raymond E. Soccio, Tomoyoshi Nakadai, William Hankey, Yue Zhao, Furong Huang, Fuwen Yuan, Hongyan Wang, Zhifen Cui, Benjamin Sunkel, Dayong Wu, Richard K. Dzeng, Jennifer M. Thomas-Ahner, Tim H.M. Huang, Steven K. Clinton, Jiaoti Huang, Mitchell A. Lazar, Victor X. Jin, Robert G. RoederQianben Wang

Department of Molecular Medicine

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	4450-4463
Number of pages	14
Journal	Nucleic acids research
Volume	50
Issue number	8
DOIs	https://doi.org/10.1093/nar/gkac246
State	Published - May 6 2022

ASJC Scopus subject areas

Genetics

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10.1093/nar/gkac246

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Chen, Z., Ye, Z., Soccio, R. E., Nakadai, T., Hankey, W., Zhao, Y., Huang, F., Yuan, F., Wang, H., Cui, Z., Sunkel, B., Wu, D., Dzeng, R. K., Thomas-Ahner, J. M., Huang, T. H. M., Clinton, S. K., Huang, J., Lazar, M. A., Jin, V. X., ... Wang, Q. (2022). Phosphorylated MED1 links transcription recycling and cancer growth. Nucleic acids research, 50(8), 4450-4463. https://doi.org/10.1093/nar/gkac246

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 2022, 'Phosphorylated MED1 links transcription recycling and cancer growth', Nucleic acids research, vol. 50, no. 8, pp. 4450-4463. https://doi.org/10.1093/nar/gkac246

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title = "Phosphorylated MED1 links transcription recycling and cancer growth",

abstract = "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 = "Zhong Chen and Zhenqing Ye and Soccio, {Raymond E.} and Tomoyoshi Nakadai and William Hankey and Yue Zhao and Furong Huang and Fuwen Yuan and Hongyan Wang and Zhifen Cui and Benjamin Sunkel and Dayong Wu and Dzeng, {Richard K.} and Thomas-Ahner, {Jennifer M.} and Huang, {Tim H.M.} and Clinton, {Steven K.} and Jiaoti Huang and Lazar, {Mitchell A.} and Jin, {Victor X.} and Roeder, {Robert G.} and Qianben Wang",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s) 2022. Published by Oxford University Press on behalf of Nucleic Acids Research.",

year = "2022",

month = may,

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doi = "10.1093/nar/gkac246",

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T1 - Phosphorylated MED1 links transcription recycling and cancer growth

AU - Chen, Zhong

AU - Ye, Zhenqing

AU - Soccio, Raymond E.

AU - Nakadai, Tomoyoshi

AU - Hankey, William

AU - Zhao, Yue

AU - Huang, Furong

AU - Yuan, Fuwen

AU - Wang, Hongyan

AU - Cui, Zhifen

AU - Sunkel, Benjamin

AU - Wu, Dayong

AU - Dzeng, Richard K.

AU - Thomas-Ahner, Jennifer M.

AU - Huang, Tim H.M.

AU - Clinton, Steven K.

AU - Huang, Jiaoti

AU - Lazar, Mitchell A.

AU - Jin, Victor X.

AU - Roeder, Robert G.

AU - Wang, Qianben

PY - 2022/5/6

Y1 - 2022/5/6

N2 - 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.

AB - 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.

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Phosphorylated MED1 links transcription recycling and cancer growth

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