DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization

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...

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Bibliographic Details
Published in:eLife 2015-03, Vol.4
Main Authors: Papp, Stephanie J, Huber, Anne-Laure, Jordan, Sabine D, Kriebs, Anna, Nguyen, Madelena, Moresco, James J, Yates, John R, Lamia, Katja A
Format: Article
Language:English
Subjects:
Animals
Biochemistry
Cell Line
Circadian Clocks - genetics
Circadian rhythm
Circadian rhythms
cryptochrome
Cryptochromes
Cryptochromes - metabolism
Cryptochromes - physiology
Deoxyribonucleic acid
DNA
DNA Damage
DNA repair
Enzymes
Gene expression
Gene regulation
Genotoxicity
Hausp
Herpes viruses
Kinases
Mammals
Mass spectrometry
Medical research
Mice
Neuroscience
Phosphorylation
Physiology
Protein Binding
Protein Stability
Proteins
Repressors
Scientific imaging
Transcription factors
Transcription, Genetic
Ubiquitin
Ubiquitin-Specific Peptidase 7
Ubiquitin-Specific Proteases - metabolism
Ubiquitin-Specific Proteases - physiology
Ubiquitin-specific proteinase
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.04883