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 journalArticle

12 Citations (Scopus)

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)
JournaleLife
Volume4
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Cryptochromes
Circadian Clocks
DNA Damage
Clocks
Stabilization
DNA
DNA Repair Enzymes
Deoxyribodipyrimidine Photo-Lyase
Ubiquitin-Specific Proteases
Phosphorylation
Post Translational Protein Processing
Viruses
DNA Repair
Repair
Light

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

Cite this

Papp, S. J., Huber, A. L., Jordan, S. D., Kriebs, A., Nguyen, M., Moresco, J. J., ... Lamia, K. A. (2015). DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. eLife, 4. https://doi.org/10.7554/eLife.04883

DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. / Papp, Stephanie J.; Huber, Anne Laure; Jordan, Sabine D.; Kriebs, Anna; Nguyen, Madelena; Moresco, James J.; Yates, John R.; Lamia, Katja A.

In: eLife, Vol. 4, 01.01.2015.

Research output: Contribution to journalArticle

Papp, SJ, Huber, AL, Jordan, SD, Kriebs, A, Nguyen, M, Moresco, JJ, Yates, JR & Lamia, KA 2015, 'DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization', eLife, vol. 4. https://doi.org/10.7554/eLife.04883
Papp, Stephanie J. ; Huber, Anne Laure ; Jordan, Sabine D. ; Kriebs, Anna ; Nguyen, Madelena ; Moresco, James J. ; Yates, John R. ; Lamia, Katja A. / DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization. In: eLife. 2015 ; Vol. 4.
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