CRY2 and FBXL3 Cooperatively Degrade c-MYC
(2016) In Molecular Cell 64(4). p.774-789- Abstract
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... (More)
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.
(Less)
- author
- organization
- publishing date
- 2016-11-17
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- circadian clock, circadian rhythm, CRY2, cryptochrome, FBXL3, MYC, ubiquitin
- in
- Molecular Cell
- volume
- 64
- issue
- 4
- pages
- 16 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:84995578417
- pmid:27840026
- wos:000389515400014
- ISSN
- 1097-2765
- DOI
- 10.1016/j.molcel.2016.10.012
- language
- English
- LU publication?
- no
- id
- 2173fadf-9be4-41da-afb9-43606ccecbbf
- date added to LUP
- 2016-12-07 08:55:57
- date last changed
- 2024-09-22 03:40:34
@article{2173fadf-9be4-41da-afb9-43606ccecbbf, abstract = {{<p>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.</p>}}, author = {{Huber, Anne Laure and Papp, Stephanie J. and Chan, Alanna B. and Henriksson, Emma and Jordan, Sabine D. and Kriebs, Anna and Nguyen, Madelena and Wallace, Martina and Li, Zhizhong and Metallo, Christian M. and Lamia, Katja A.}}, issn = {{1097-2765}}, keywords = {{circadian clock; circadian rhythm; CRY2; cryptochrome; FBXL3; MYC; ubiquitin}}, language = {{eng}}, month = {{11}}, number = {{4}}, pages = {{774--789}}, publisher = {{Cell Press}}, series = {{Molecular Cell}}, title = {{CRY2 and FBXL3 Cooperatively Degrade c-MYC}}, url = {{http://dx.doi.org/10.1016/j.molcel.2016.10.012}}, doi = {{10.1016/j.molcel.2016.10.012}}, volume = {{64}}, year = {{2016}}, }