Twenty-four hour rhythms in our physical and ecological environment present a challenge to the maintenance of physiological homeostasis. Circadian clocks enable organisms from bacteria to humans to predict and prepare for these daily fluctuations and enhance survival and overall health. Circadian rhythms play important roles in many aspects of mammalian physiology including glucose, drug, and tumor metabolism. Circadian disruption, such as that caused by shift work, increases the risk of many pathologies, including metabolic disease and cancer. We are dedicated to understanding the molecular mechanisms underlying these phenomena.
CIRCADIAN RHYTHMS AND EXERCISE
Regular exercise is an important component of a healthy lifestyle. Over the last 20 years, we and others have demonstrated that circadian clocks play a major role in synchronizing physiological processes with daily fluctuations in metabolic demand. For example, the liver circadian clock increases glucose production to compensate for the lack of dietary sugar intake during sleep. Recently, several groups have demonstrated that circadian rhythms influence both the health benefits of exercise and maximum exercise capacities.
We have found that circadian clocks in muscles alter the types of metabolites that are used for energy production during exercise at different times of the day. Furthermore, we demonstrated that the circadian repressors CRY1 and CRY2 regulate transcription factors involved in exercise, including nuclear hormone receptors like PPAR∂ and hypoxia inducible factors (HIFs). Further, time of day profoundly impacts the response to exercise training. We are currently investigating the muscle-intrinsic roles of CRYs in these phenomena.
HOW DOES CIRCADIAN DISRUPTION INCREASE CANCER RISK?
Epidemiological studies have shown that chronic circadian disruption, such as that caused by shift work, leads to a small but significant increase in cancer risk. Furthermore, tumor formation in several mouse models of cancer is exacerbated by exposure to conditions that mimic rotating shift work in the laboratory.
Because of the evolutionary relationship between cryptochromes (CRY1 and CRY2) and bacterial DNA repair enzymes, we and others have had a long-standing interest in understanding whether they retain a relationship to the DNA damage response. We found that CRY2 facilitates ubiquitin-mediated degradation of c-MYC, E2F family transcription factors, and the DNA damage responsive kinase TLK2. Recently, we described several cancer-associated point mutations in CRY2 that suppress P53. We are investigating whether and how these findings relate to the observed link between circadian disruption and elevated cancer risk using a combination of human cancer genome data, mouse genetics and biochemistry, with a particular focus on lung cancer, lymphoma, and renal cell carcinoma.
QUANTIFYING THE IMPACT OF CIRCADIAN DISRUPTION ON GENOME INTEGRITY
To avoid large numbers of mutations, mammalian cells utilize a variety of pathways to protect the genome from mutations that arise during normal cell proliferation and/or following exposure to diverse DNA damaging agents. Intriguingly, 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). We are measuring mutation rates in wildtype and Cry2-/- littermate mice subjected to standard housing conditions or to environmental circadian disruption in collaboration with the Lohmueller lab at the University of California, Los Angeles, using methods that are well established in population genetics.