Skip Navigation
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Internet Explorer is no longer a supported browser.

This website may not display properly with Internet Explorer. For the best experience, please use a more recent browser such as the latest versions of Google Chrome, Microsoft Edge, and/or Mozilla Firefox. Thank you.

Your Environment. Your Health.

QUANTIFYING THE IMPACT OF CIRCADIAN DISRUPTION ON GENOME STABILITY

Export to Word (http://www.niehs.nih.gov//portfolio/index.cfm/portfolio/grantdetail/grant_number/R21ES031000/format/word)
Principal Investigator: Lamia, Katja A
Institute Receiving Award Scripps Research Institute
Location La Jolla, CA
Grant Number R21ES031000
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 15 Aug 2019 to 31 Jul 2021
DESCRIPTION (provided by applicant): PROJECT SUMMARY (DESCRIPTION)    Mutation is the source of genetic variation and can give rise to disease, aging, and cancer. Mammals have so-­ phisticated pathways to reduce mutation by repairing errors occurring during DNA replication as well as dam-­ age due to environmental effects. While many biological pathways have been extensively studied, other un-­ known DNA repair pathways may remain undiscovered. We hypothesize that one such pathway is the circadi-­ an clock pathway. The scientific premise of our proposal is that studies have shown mice harboring genetic  disruption of circadian clock function exhibit increased tumor formation and accelerated aging. Further, epide-­ miological studies suggest circadian disruption is a likely carcinogen. While mammalian core circadian clock  proteins CRY1 and CRY2 seem to lack catalytic DNA repair activity, they evolved from bacterial light-­activated  DNA repair enzymes (CPD photolyases). Lastly, we have recently shown that CRY2-­deficient cells contain  significantly elevated numbers of double strand breaks, and Cry2-­/-­ mice are uniquely born at sub-­Mendelian  ratios, suggesting an increase in lethal mutations.     Based on these observations and this premise, we hypothesize that mammalian CRY2 has maintained a func-­ tional connection to protecting genome integrity, and that disruption of this function increases genome-­wide  mutation rates, which in turn contributes to elevated cancer risk caused by environmental circadian disruption.  To test this hypothesis, we will measure mutation rates in wildtype and Cry2-­/-­ littermate mice subjected to  standard housing conditions or to environmental circadian disruption by performing whole-­genome sequencing.     In Aim 1 of this project, we will test whether Cry2-­/-­ mice have elevated germline mutation rates compared wild-­ type. To do this, we will perform three independent crosses from which we will sequence both parents and  three of their progeny and count the number of de novo mutations present in the progeny. We will compare the  number of accumulated mutations in progeny born to Cry-­deficient parents to that in offspring born to wild-­type  parents. Because mutations may not occur equally in male and female parents, we will examine offspring from  male or female Cry2-­deficient parents bred to wildtype partners. In Aim 2 of this project, we will test whether  environmental circadian disruption increases germline mutation rates. To do this, we will breed a mouse ex-­ posed to chronic jet lag light cycles to a wild-­type parent and sequence the genomes of the parents and 3 of  the progeny. We will compare the number of de novo mutations to that number in offspring born to parents ex-­ posed to normal light-­dark cycles. Successful completion of this research will indicate whether environmental  disruption of circadian clocks can affect genome integrity, laying the groundwork for further studies of the  mechanism of circadian disruption on disease.    
Science Code(s)/Area of Science(s) Primary: 23 - Circadian Rhythms
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications See publications associated with this Grant.
Program Officer Leslie Reinlib
Back
to Top