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

ELife
Stephanie J PappKatja A Lamia

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.

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Methods Mentioned

BETA
ubiquitination
immunoprecipitation
deubiquitination
deubiquitinate
transfection
PCR
ChIP

Software Mentioned

PatternLab for Proteomics
Pattern Lab for Proteomics
Gene Set Enrichment Analysis
Actimetrics Lumicycle Analysis
RawXtract
Pattern Lab
DTASelect
Actimetrics Lumicycle Data Collection

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