Journal
MOLECULAR CELL
Volume 64, Issue 4, Pages 774-789Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2016.10.012
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Funding
- NIH [DK090188, DK097164, CA188652]
- Kinship Foundation
- Sidney Kimmel Cancer Research Foundation
- Lung Cancer Research Foundation
- Swedish Research Council
- Deutsche Forschungsgemeinschaft
- American Heart Association [15POST22510020]
- NIGMS [P41-GM103311]
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For many years, a connection between circadian clocks and cancer has been postulated. Here we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, although the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation. Their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. We demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.
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