CRY2 and FBXL3 Cooperatively Degrade c-MYC.

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. Copyright © 2016 Elsevier Inc. All rights reserved.

Citation

Anne-Laure Huber, Stephanie J Papp, Alanna B Chan, Emma Henriksson, Sabine D Jordan, Anna Kriebs, Madelena Nguyen, Martina Wallace, Zhizhong Li, Christian M Metallo, Katja A Lamia. CRY2 and FBXL3 Cooperatively Degrade c-MYC. Molecular cell. 2016 Nov 17;64(4):774-789

Mesh Tags

Substances

PMID: 27840026

search → result