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DNA damage shifts circadian clock time via Hausp-dependent Cry1 stabilization
Stephanie J Papp1, Anne-Laure Huber1, Sabine D Jordan1
1Department of Chemical Physiology, Scripps Research Institute, La Jolla, United States.
Elife
|March 11, 2015
Summary
Cryptochromes (Cry1/2), evolved from DNA repair enzymes, now protect genomic integrity by regulating gene expression in response to DNA damage, with distinct roles for Cry1 and Cry2.
Area of Science:
- Molecular Biology
- Chronobiology
- Genetics
Background:
- Cryptochromes (Cry1/2) are circadian transcriptional repressors that evolved from bacterial DNA repair enzymes (photolyases).
- While Cry1/2 have lost direct DNA repair activity, their ancestral link suggests a role in maintaining genomic integrity.
- The posttranslational modifications and distinct functions of Cry1 and Cry2 in response to cellular stress remain incompletely understood.
Purpose of the Study:
- To investigate the role of Cryptochromes (Cry1/2) in genomic integrity maintenance following genotoxic stress.
- To elucidate the distinct mechanisms by which Cry1 and Cry2 respond to DNA damage.
- To understand how Cry1/2 coordinate transcriptional responses to genotoxic stress.
Main Methods:
- Utilized cell-based assays to examine Cry1 and Cry2 stability and localization under genotoxic stress conditions.
- Investigated the role of Herpes virus associated ubiquitin-specific protease (Hausp, also known as Usp7) in Cry1 deubiquitination.
- Analyzed the interaction between Cry2 and Fbxl3 upon DNA damage.
- Assessed transcriptional responses and DNA damage accumulation in Cry1 and Cry2 knockout cells.
Main Results:
- Genotoxic stress induces Cry1 phosphorylation and deubiquitination by Hausp, leading to Cry1 stabilization and circadian clock resetting.
- DNA damage promotes Cry2 interaction with Fbxl3, resulting in Cry2 destabilization, thereby increasing the Cry1/Cry2 ratio.
- Transcriptional responses to genotoxic stress are enhanced in Cry1 knockout cells and reduced in Cry2 knockout cells.
- Cry2 knockout cells exhibit accumulation of damaged DNA, highlighting a critical role for Cry2 in DNA repair pathways.
Conclusions:
- Cry1 and Cry2 have adapted from DNA repair enzymes to protect genomic integrity through posttranslational modifications and coordinated transcriptional regulation.
- Distinct roles of Cry1 (stabilization, clock resetting) and Cry2 (destabilization, DNA damage accumulation) emerge following genotoxic stress.
- The Cry1/Cry2 axis plays a crucial role in cellular response to DNA damage, ensuring genomic stability.
Keywords:
DNA damageHauspbiochemistrycircadian rhythmcryptochromemouseneurosciencephosphorylationubiquitinMore Related Videos
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