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Cereblon attenuates DNA damage-induced apoptosis by regulating the transcription-independent function of p53

Liang Zhou1, Guoqiang Xu2

  • 1Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, Jiangsu, 215123, China.

Cell Death & Disease
|January 27, 2019
PubMed

Insights

Cereblon (CRBN) protects cells from DNA damage-induced apoptosis by interacting with p53 and preventing its association with anti-apoptotic proteins. This discovery reveals a new role for CRBN in DNA damage response.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • Cereblon (CRBN) is a key component of the CUL4-RING E3 ubiquitin ligase complex.
  • CRBN is utilized for targeted protein degradation in cancer therapy.
  • The physiological roles and DNA damage response mechanisms of CRBN are not well understood.

Purpose of the Study:

  • To investigate the function of CRBN in the cellular response to DNA damage.
  • To elucidate the molecular mechanism by which CRBN regulates DNA damage-induced apoptosis.
  • To explore the in vivo relevance of CRBN's role in DNA damage response.

Main Methods:

  • Cellular apoptosis assays in response to DNA damage (etoposide treatment).
  • Co-immunoprecipitation to study protein-protein interactions (CRBN, p53, Bcl-2, Bcl-XL).
  • Mitochondrial membrane potential assessment and caspase cleavage analysis.
  • Evaluation of etoposide sensitivity in Crbn knockout mice.

Main Results:

  • CRBN plays a protective role against DNA damage-induced apoptosis.
  • CRBN directly interacts with p53, suppressing its interaction with Bcl-2 and Bcl-XL.
  • CRBN depletion enhances p53-Bcl-2/Bcl-XL interaction, leading to increased apoptosis and reduced mitochondrial membrane potential.
  • Crbn knockout mice show increased mortality upon etoposide challenge, indicating impaired DNA damage response.

Conclusions:

  • CRBN inhibits DNA damage-induced apoptosis through a novel mechanism involving direct interaction with p53.
  • This interaction prevents p53 from binding to anti-apoptotic proteins, thereby protecting cells from programmed cell death.
  • CRBN has a significant physiological role in protecting against DNA damage, both in vitro and in vivo.
  • Findings suggest potential therapeutic applications of CRBN modulation in DNA damage-associated diseases.

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