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| 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 |