CRY2missense 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 SCFFBXL3-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 is the primary mechanism by which they influence cell growth.

Circadian rhythms and cancers: the intrinsic links and therapeutic potentials

“…In addition, previous studies have revealed CLOCK and BMAL1 as key regulators for acute myeloid leukemia (AML) by contributing to proliferation and stemness [ 66 , 67 ]. Moreover, deletions of Cry1 and Cry2 diminished tumor development in p53 null mice possibly due to triple mutant-induced genotoxic stress [ 68 , 69 ]. Taken together, the dual function of clock genes, either as oncogenes or as tumor suppressors, may be attributed to tissue-specific mechanisms and implies the existence of intricate clock-dependent networks, which are involved in the maintenance of homeostasis during different tumor stages.…”