It’s About Time: Advances in Understanding the Circadian Regulation of DNA Damage and Repair in Carcinogenesis and Cancer Treatment Outcomes

The circadian rhythm is established by a coordinated network of peripheral clocks interlocked and regulated by a central pacemaker. This network is maintained by the rhythmic expression of core clock genes, which in turn generate oscillatory expression patterns of different sets of target proteins in a tissue-specific manner. Precise regulation of biological processes driven by the body’s circadian network in response to periodic changes in the environment determines healthy life. The delicate balance in the cycling of enzymes, metabolites, cofactors, and immune regulators is essential to achieve cellular homeostasis. Disruption of this circadian homeostasis has been linked with the development and progression of various diseases including cancer. Over the years, circadian regulation of drug metabolism and processing has been employed in the treatment of diabetes, hypertension, peptic ulcers, and allergic rhinitis. Although time dictated drug administration was demonstrated many decades ago, its application in cancer treatment is limited due to insufficient mechanistic data supporting experimental results and inconsistency between clinical trials. However, timed administration of anti-cancer drugs is rapidly gaining attention as studies with animal and human models unveil molecular intricacies involved in the circadian control of biological pathways. In this regard, striking a balance between maximizing tumor responsiveness and minimizing side effects is crucial to achieve positive patient outcomes. This review focuses on regulation of the circadian clock in carcinogenesis outcomes through DNA damage and repair mechanisms and its application in therapy with specific emphasis on skin and breast cancers.