Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity

Yin Fang; Yan Wang; Benjamin M Spector; Xue Xiao; Chao Yang; Ping Li; Yuan Yuan; Ping Ding; Zhi-Xiong Xiao; Peixuan Zhang; Tong Qiu; Xiaofeng Zhu; David H Price; Qintong Li

doi:10.1016/j.isci.2022.104844

Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity

iScience. 2022 Aug 4;25(9):104844. doi: 10.1016/j.isci.2022.104844. eCollection 2022 Sep 16.

Authors

Yin Fang¹, Yan Wang¹, Benjamin M Spector², Xue Xiao¹, Chao Yang^{3

4}, Ping Li¹, Yuan Yuan^{3

4}, Ping Ding^{3

4}, Zhi-Xiong Xiao⁵, Peixuan Zhang¹, Tong Qiu¹, Xiaofeng Zhu⁵, David H Price², Qintong Li¹

Affiliations

¹ Departments of Pediatrics and Obstetrics & Gynecology, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Development and Related Diseases of Women and Children Key Laboratory of Sichuan Province, Center of Growth, Metabolism and Aging, College of Life Sciences, State Key Laboratory of Biotherapy and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu 610041, China.
² Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
³ Division of Bioinformatics, Sichuan Cunde Therapeutics, Chengdu 610093, China.
⁴ Non-coding RNA and Drug Discovery Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu 610500, China.
⁵ Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610064, China.

Abstract

Testicular germ cell tumors and closely related embryonal stem cells are exquisitely sensitive to cisplatin, a feature thought to be linked to their pluripotent state and p53 status. It remains unclear whether and how cellular state is coordinated with p53 to confer cisplatin sensitivity. Here, we report that positive transcription elongation factor b (P-TEFb) determines cell fate upon DNA damage. We find that cisplatin rapidly activates P-TEFb by releasing it from inhibitory 7SK small nuclear ribonucleoprotein complex. P-TEFb directly phosphorylates pluripotency factor estrogen-related receptor beta (ESRRB), and induces its proteasomal degradation to enhance pro-survival glycolysis. On the other hand, P-TEFb is required for the transcription of a substantial portion of p53 target genes, triggering cell death during prolonged cisplatin treatment. These results reveal previously underappreciated roles of P-TEFb to coordinate the DNA damage response. We discuss the implications for using P-TEFb inhibitors to treat cancer and ameliorate cisplatin-induced ototoxicity.

Keywords: Cancer; Molecular biology; Molecular mechanism of gene regulation.

Grants and funding

R35 GM126908/GM/NIGMS NIH HHS/United States