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

Stephanie J. Papp, Anne Laure Huber, Sabine D. Jordan, Anna Kriebs, Madelena Nguyen, James J. Moresco, John R. Yates, Katja A. Lamia

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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.

Original languageEnglish (US)
Article numbere04883
JournaleLife
Volume4
DOIs
StatePublished - 2015
Externally publishedYes

Keywords

  • DNA damage
  • Hausp
  • biochemistry
  • circadian rhythm
  • cryptochrome
  • mouse
  • neuroscience
  • phosphorylation
  • ubiquitin

ASJC Scopus subject areas

  • General Immunology and Microbiology
  • General Biochemistry, Genetics and Molecular Biology
  • General Neuroscience

Fingerprint

Dive into the research topics of 'DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization'. Together they form a unique fingerprint.

Cite this