title: DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization.
abstract: The circadian transcriptional repressors cryptochrome 1 (Cry1) and 2 (Cry2) evolved from photolyases, bacterial light-activated DNA repair enzymes. In this study, we report that while they have lost DNA repair activity, Cry1/2 adapted to protect genomic integrity by responding to DNA damage through posttranslational modification and coordinating the downstream transcriptional response. We demonstrate that genotoxic stress stimulates Cry1 phosphorylation and its deubiquitination by Herpes virus associated ubiquitin-specific protease (Hausp, a.k.a Usp7), stabilizing Cry1 and shifting circadian clock time. DNA damage also increases Cry2 interaction with Fbxl3, destabilizing Cry2. Thus, genotoxic stress increases the Cry1/Cry2 ratio, suggesting distinct functions for Cry1 and Cry2 following DNA damage. Indeed, the transcriptional response to genotoxic stress is enhanced in Cry1-/- and blunted in Cry2-/- cells. Furthermore, Cry2-/- cells accumulate damaged DNA. These results suggest that Cry1 and Cry2, which evolved from DNA repair enzymes, protect genomic integrity via coordinated transcriptional regulation.
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Papp
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Huber
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Sabine D
authors.initials: SD
authors.lastname: Jordan
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Anna
authors.initials: A
authors.lastname: Kriebs
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Madelena
authors.initials: M
authors.lastname: Nguyen
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Moresco
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
authors.forename: Katja A
authors.initials: KA
authors.lastname: Lamia
mesh_terms: D000818:Animals; D002460:Cell Line; D057906:Circadian Clocks / Q000235:genetics*; D056931:Cryptochromes / Q000378:metabolism / Q000502:physiology*; D004249:DNA Damage; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D055550:Protein Stability; D014158:Transcription, Genetic; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism / Q000502:physiology*
chemical_list: C538964:Cry1 protein, mouse; D056931:Cryptochromes; D000076084:Ubiquitin-Specific Peptidase 7; D064570:Ubiquitin-Specific Proteases; C579190:Usp7 protein, mouse
keywords: DNA damage; Hausp; biochemistry; circadian rhythm; cryptochrome; mouse; neuroscience; phosphorylation; ubiquitin