Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 118, Issue 27, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2101416118
Keywords
cryptochromes; circadian clocks; tumor suppressor protein P53
Categories
Funding
- NIH [CA211187, GM107069]
- University of California, Santa Cruz (UCSC) graduate division
- University of California Office of the President (UCOP)
- UCSC Chancellor's Postdoctoral Fellowship
- HHMI Gilliam Fellowship
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Disruption of circadian rhythms can increase the risk of various cancers. Mutations in the CRY2 gene found in human cancers have been shown to accelerate cell growth in mouse fibroblasts expressing high levels of c-MYC. These mutations also have divergent effects on circadian rhythms and interaction with SCFFBXL3.
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.
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