文章基本信息

标题：Dynamic regulation of P-TEFb by 7SK snRNP is integral to the DNA damage response to regulate chemotherapy sensitivity
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作者：Yin Fang ; Yan Wang ; Benjamin M. Spector 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2022
卷号：25
期号：9
页码：1-26
DOI：10.1016/j.isci.2022.104844
语种：English
出版社：Elsevier
摘要：SummaryTesticular 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.Graphical abstractDisplay OmittedHighlights•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 deathMolecular biology; Molecular mechanism of gene regulation; Cancer