CRY2 missense mutations suppress P53 and enhance cell growth

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)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.

Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers

“…However, CRY2 up-regulation is described in chemoresistant colorectal cancer patients [ 120 ]. In addition, Chan et al [ 121 ] showed that mutations in CRY2 led to p53 suppression and provided cell proliferation. Thus, the different expression levels of CRY1 and CRY2 appear to impact leukemic cells over different pathways, showing the need for further investigation into these mechanisms in order to elucidate their value as a leukemic biomarker [ 122 ].…”

Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer

“…The Apc locus is a known target of point mutations, insertions, deletions, and LOH events, which have been described to drive tumor progression (14,63). In addition, the circadian clock is reported to be involved in the DNA damage response and DNA repair (39,(64)(65)(66)(67). Disruption of the clock may therefore accelerate mutagenic burden.…”

“…The circadian clock maintains cellular homeostasis and systemic physiology (31)(32)(33). However, altered circadian gene expression signatures are associated with several diseases including multiple cancer types (34)(35)(36)(37)(38)(39)(40)(41)(42). Human data from The Cancer Genome Atlas (TCGA) show a significant correlation between a subset of deregulated core clock genes and oncogenic driver pathways, survival rates, and tumor staging in 32 different cancer types (43).…”

Structural and Chemical Biology Approaches Reveal Isoform-Selective Mechanisms of Ligand Interactions in Mammalian Cryptochromes

“…KS15 has anti-proliferative effects on breast cancer MCF-7 cells by increasing p53 and Bax gene expression (Chun et al, 2015). Considering that CRY1 and CRY2 have been associated with p53 suppression or degradation in other cancers (Chan et al, 2021;Jia et al, 2021) and that Cry1 and Cry2 knockout in p53 mutant mice reduces cancer risk (Ozturk et al, 2009), KS15, or its derivatives (Jeong et al, 2021) may be efficacious in the treatment of several cancers, in addition to MCF-7 breast cancer. Together, these results identified CRYs as promising targets of small-molecule compounds.…”

“…CRY dysfunction has been implicated in diseases, such as circadian sleep disorders (Hirano et al, 2016;Patke et al, 2017) and diabetes (Zhang et al, 2010;Lamia et al, 2011). Furthermore, CRY1 and CRY2 isoforms have been differentially associated with cancer and may function as pro-or antitumorigenic factors depending on the type of cancer (Chan and Lamia, 2020;Chan et al, 2021;Shafi et al, 2021). CRYs therefore represent attractive drug targets for the treatment of CRY-mediated and circadian clock-related diseases.…”