Journal article
Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity
iScience, Vol.25(9), p.104844
09/16/2022
DOI: 10.1016/j.isci.2022.104844
PMCID: PMC9399290
PMID: 36034227
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.
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•P-TEFb regulates pro-survival and pro-death pathways during DNA damage response•P-TEFb promotes ESRRB proteasomal degradation to enhance pro-survival glycolysis•P-TEFb induces a substantial portion of p53 target genes to trigger cell death•Chemical inhibitors of P-TEFb blocks cisplatin- or UV-induced cell death
Molecular biology; Molecular mechanism of gene regulation; Cancer
Details
- Title: Subtitle
- Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity
- Creators
- Yin Fang - Sichuan UniversityYan Wang - Sichuan UniversityBenjamin M. Spector - University of IowaXue Xiao - Sichuan UniversityChao Yang - Division of Bioinformatics, Sichuan Cunde Therapeutics, Chengdu 610093, ChinaPing Li - Sichuan UniversityYuan Yuan - Division of Bioinformatics, Sichuan Cunde Therapeutics, Chengdu 610093, ChinaPing Ding - Division of Bioinformatics, Sichuan Cunde Therapeutics, Chengdu 610093, ChinaZhi-Xiong Xiao - Sichuan UniversityPeixuan Zhang - Sichuan UniversityTong Qiu - Sichuan UniversityXiaofeng Zhu - Sichuan UniversityDavid H. Price - Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USAQintong Li - Sichuan University
- Resource Type
- Journal article
- Publication Details
- iScience, Vol.25(9), p.104844
- DOI
- 10.1016/j.isci.2022.104844
- PMID
- 36034227
- PMCID
- PMC9399290
- NLM abbreviation
- iScience
- ISSN
- 2589-0042
- eISSN
- 2589-0042
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: GM126908; DOI: 10.13039/501100001809, name: National Natural Science Foundation of China, award: 31971141, 82071651; DOI: 10.13039/501100004829, name: Department of Science and Technology of Sichuan Province, award: 2020YFS0460, 2021YJ0012
- Language
- English
- Date published
- 09/16/2022
- Academic Unit
- Biochemistry and Molecular Biology
- Record Identifier
- 9984288724602771
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