DNA damage and the circadian clock

Abstract

The role of the circadian clock has already been demonstrated for virtually all physiological processes, but it was only recently shown that cells were more sensitive to DNA damage at specific times of the day; that the peak of synthesis of mRNA and proteins of genes coding for products involved directly or indirectly in DNA repair was differentially timed in different tissues; and that the growth of some types of cancer followed a circadian pattern. The paper reviews the specificities of the clockwork mechanism in living cells associated with repair of DNA damage with regards to its role in ageing and carcinogenesis. The role of heritable polymorhisms and somatic mutations in the risk for development of common diseases (cancer, but also other types of diseases and conditions, such as obesity and metabolic syndrome), their course and the possible outcomes is reviewed in animal models and in man. The circadian oscillations in the levels of major proteins of DNA-damage related signalling and DNA repair are discussed in relation to differential mechanisms of defence against genotoxic damage. The paper outlines the modern concept of ''chronotherapy'' - that is, anticancer therapy administered at specific times of the day/ night cycle that could be associated with better outcomes in some patients and analyses the individual variance in the tolerability of chronotherapy vs. maximum-dose anticancer therapy.

Keywords

• DNA damage
• circadian clock