title: CRY2 and FBXL3 Cooperatively Degrade c-MYC.
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 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.
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huber
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Papp
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Alanna B
authors.initials: AB
authors.lastname: Chan
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA; Department of Clinical Sciences, CRC, Lund University, Malmö 20502, Sweden.
authors.forename: Emma
authors.initials: E
authors.lastname: Henriksson
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Sabine D
authors.initials: SD
authors.lastname: Jordan
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Kriebs
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA.
authors.forename: Madelena
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Wallace
authors.affiliation: Drug Discovery Oncology Unit, Genomics Institute of the Novartis Research Foundation and Novartis Institutes for Biomedical Research, 10675 John J. Hopkins Drive, San Diego, CA 92121, USA.
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Metallo
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, MB31, La Jolla, CA 92037, USA. Electronic address: klamia@scripps.edu.
authors.forename: Katja A
authors.initials: KA
authors.lastname: Lamia
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D057906:Circadian Clocks / Q000235:genetics*; D002940:Circadian Rhythm / Q000235:genetics; D056931:Cryptochromes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044842:Cullin Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005347:Fibroblasts; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D055550:Protein Stability; D017433:Protein Structure, Secondary; D059748:Proteolysis; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; C538967:Cry2 protein, mouse; D056931:Cryptochromes; C100318:Cullin 1; D044842:Cullin Proteins; D044783:F-Box Proteins; C519794:Fbxl3 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C540494:RBX1 protein, mouse; D044786:S-Phase Kinase-Associated Proteins
keywords: CRY2; FBXL3; MYC; circadian clock; circadian rhythm; cryptochrome; ubiquitin