CRY2 missense mutations suppress P53 and enhance cell growth
Menée in vitro et à l'aide d'un modèle murin et de données du projet "The Cancer Genome Atlas", cette étude met en évidence un mécanisme par lequel des mutations faux-sens au niveau du gène CRY2 suppriment l'expression de p53 et augmentent la croissance des cellules fibroblastiques transformées par le proto-oncogène MYC
Disruption of circadian rhythms enhances cancer risk, but the underlying mechanisms are largely unknown. The circadian repressors CRY1 and CRY2 evolved from light-activated DNA-repair enzymes, suggesting that they may be involved. Here, we demonstrate that missense mutations in CRY2 reported in The Cancer Genome Atlas suppress P53 target-gene expression and enhance the growth of MYC-transformed fibroblasts. Our identification of point mutations in CRY2 in human tumors that influence P53 activity and cell growth provides evidence for a clinically relevant molecular connection between CRYs and P53. Furthermore, these mutants will enable new strategies to investigate underlying molecular mechanisms and inform a growing effort to identify selective chemical modulators of CRY1 and/or CRY2.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)FBXL3-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 SCFFBXL3. 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.RNA-seq data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (accession no. GSE165647).