Missense Mutations Suppress P53 and Enhance Cell Growth

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2021 Jun 29

PMID 34183418

Citations 14

Authors

Alanna B Chan

Gian Carlo G Parico

Jennifer L Fribourgh

Lara H Ibrahim

Michael J Bollong

Carrie L Partch

Katja A Lamia

Affiliations

Soon will be listed here.

Abstract

Disruption of circadian rhythms increases the risk of several types of cancer. Mammalian cryptochromes (CRY1 and CRY2) are circadian transcriptional repressors that are related to DNA-repair enzymes. While CRYs lack DNA-repair activity, they modulate the transcriptional response to DNA damage, and CRY2 can promote SKP1 cullin 1-F-box (SCF)-mediated ubiquitination of c-MYC and other targets. Here, we characterize five mutations in CRY2 observed in human cancers in The Cancer Genome Atlas. We demonstrate that two orthologous mutations of mouse CRY2 (D325H and S510L) accelerate the growth of primary mouse fibroblasts expressing high levels of c-MYC. Neither mutant affects steady-state levels of overexpressed c-MYC, and they have divergent impacts on circadian rhythms and on the ability of CRY2 to interact with SCF Unexpectedly, stable expression of either CRY2 D325H or of CRY2 S510L robustly suppresses P53 target-gene expression, suggesting that this may be a primary mechanism by which they influence cell growth.

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