Details

Autor(en) / Beteiligte

• Huber, Anne-Laure
• Papp, Stephanie J.
• Chan, Alanna B.
• Henriksson, Emma
• Jordan, Sabine D.
• Kriebs, Anna
• Nguyen, Madelena
• Wallace, Martina
• Li, Zhizhong
• Metallo, Christian M.
• Lamia, Katja A.

Titel

CRY2 and FBXL3 Cooperatively Degrade c-MYC

Ist Teil von

• Molecular cell, 2016-11, Vol.64 (4), p.774-789

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2016

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •Loss of CRY2 stabilizes c-MYC and enhances cellular transformation•CRY2 can function as a co-factor for the SCF substrate adaptor FBXL3•c-MYC phosphorylated on threonine 58 (T58) interacts with CRY2•SCFFBXL3+CRY2 promotes the ubiquitylation and turnover of c-MYC Circadian disruption increases the risk of many types of cancer. Huber et al. demonstrate that the circadian clock protein CRY2 recruits T58-phosphorylated c-MYC to SCFFBXL3, thus promoting its ubiquitination and degradation. This unexpected function of CRY2 may contribute to circadian protection from tumorigenesis.