Advanced

CRY2 and FBXL3 Cooperatively Degrade c-MYC

Huber, Anne Laure; Papp, Stephanie J.; Chan, Alanna B.; Henriksson, Emma LU ; Jordan, Sabine D.; Kriebs, Anna; Nguyen, Madelena; Wallace, Martina; Li, Zhizhong and Metallo, Christian M., et al. (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)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
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
  • wos:000389515400014
ISSN
1097-2765
DOI
10.1016/j.molcel.2016.10.012
language
English
LU publication?
yes
id
2173fadf-9be4-41da-afb9-43606ccecbbf
date added to LUP
2016-12-07 08:55:57
date last changed
2017-10-22 05:23:17
@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},
  keyword      = {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},
  volume       = {64},
  year         = {2016},
}