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

Yin Fang1, Yan Wang1, Benjamin M Spector2

  • 1Departments 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.

Iscience
|August 29, 2022
PubMed

Insights

Positive Transcription Elongation Factor b (P-TEFb) dictates cell fate after DNA damage, coordinating responses to cisplatin chemotherapy. P-TEFb activation promotes survival pathways initially, then triggers cell death, offering new therapeutic targets.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Biology

Background:

  • Testicular germ cell tumors and embryonal stem cells show high sensitivity to cisplatin.
  • The interplay between cellular state, p53, and cisplatin sensitivity is not fully understood.

Purpose of the Study:

  • To elucidate the role of Positive Transcription Elongation Factor b (P-TEFb) in coordinating cellular responses to DNA damage.
  • To investigate how P-TEFb influences cell fate and cisplatin sensitivity.

Main Methods:

  • Investigated P-TEFb activation upon cisplatin treatment.
  • Assessed P-TEFb's effect on estrogen-related receptor beta (ESRRB) phosphorylation and degradation.
  • Analyzed P-TEFb's role in p53 target gene transcription.

Main Results:

  • Cisplatin rapidly activates P-TEFb by dissociating it from the 7SK small nuclear ribonucleoprotein complex.
  • P-TEFb phosphorylates and promotes proteasomal degradation of ESRRB, enhancing glycolysis for survival.
  • P-TEFb is essential for transcribing p53 target genes, leading to cell death during prolonged cisplatin exposure.

Conclusions:

  • P-TEFb plays a dual role in DNA damage response, initially promoting survival and later inducing cell death.
  • P-TEFb acts as a key coordinator between cellular state and p53-mediated responses to DNA damage.
  • Targeting P-TEFb may offer novel strategies for cancer treatment and mitigating cisplatin-induced ototoxicity.
Keywords:
CancerMolecular biologyMolecular mechanism of gene regulation

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