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Yeast As a Chassis for Developing Functional Assays to Study Human P53
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Yeast As a Chassis for Developing Functional Assays to Study Human P53

Published on: August 4, 2019

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CRY2 missense mutations suppress P53 and enhance cell growth

Alanna B Chan1, Gian Carlo G Parico2, Jennifer L Fribourgh2

  • 1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037.

Proceedings of the National Academy of Sciences of the United States of America
|June 29, 2021
PubMed

Insights

Mutations in CRY2, a protein regulating circadian rhythms, can accelerate cancer growth by suppressing P53 target genes. These findings highlight CRY2

Area of Science:

  • Molecular Biology
  • Chronobiology
  • Cancer Research

Background:

  • Disrupted circadian rhythms are linked to increased cancer risk.
  • Mammalian cryptochromes (CRY1 and CRY2) are key circadian repressors involved in DNA damage response.
  • CRY2 regulates c-MYC ubiquitination via the SCFFBXL3 complex.

Purpose of the Study:

  • To characterize five CRY2 mutations found in human cancers.
  • To investigate the functional impact of specific CRY2 mutations (D325H and S510L) on cell growth and circadian regulation.
  • To explore the mechanism by which CRY2 mutations influence cell proliferation.

Main Methods:

  • Analysis of CRY2 mutations from The Cancer Genome Atlas.
  • Characterization of mouse CRY2 mutations (D325H, S510L) in primary mouse fibroblasts.
  • Assessment of c-MYC levels, circadian rhythm impact, and SCFFBXL3 interaction.
  • Evaluation of P53 target-gene expression in cells expressing mutant CRY2.

Main Results:

  • Two mouse CRY2 mutations (D325H, S510L) accelerate fibroblast growth when c-MYC is overexpressed.
  • Mutant CRY2 proteins do not alter steady-state levels of overexpressed c-MYC.
  • Mutants exhibit differential effects on circadian rhythms and SCFFBXL3 interaction.
  • Both CRY2 D325H and CRY2 S510L robustly suppress P53 target-gene expression.

Conclusions:

  • CRY2 mutations identified in human cancers can promote cell growth.
  • Suppression of P53 target-gene expression by mutant CRY2 may be a key mechanism driving increased cell proliferation in cancer.
  • CRY2's role in circadian regulation and DNA damage response is critical in cancer development.
Keywords:
circadian clockscryptochromestumor suppressor protein P53

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