Circadian tempo: a paradigm for genome stability?
Circadian clocks are molecular time-keeping systems that underlie daily biological rhythms in anticipation of the changing light and dark cycles. These clocks mediate daily rhythms in physiology and behavior that are thought to confer an adaptive advantage for organisms. It is hypothesized that cell cycle checkpoints are gated to an intrinsic circadian clock to protect DNA from diurnal exposure to mutagens (e.g.; UV radiation peaks with daylight and dissolved genotoxins that fluctuate with feeding periods). It is proposed that DNA replication arrest in response to genotoxic stress is a likely basis for the evolution of circadian-gated DNA replication. This protective mechanism is highly conserved and can be traced along the evolutionary time-line to the early prokaryotes, unicellular eukaryotes and viruses. Peak DNA repair capacity is normally synchronous to the crest of mutagenic stress as they oscillate with respect to time. Mutator phenotypes with increased vulnerability to genotoxic stress may therefore develop when the circadian pattern of cell cycle control, DNA repair or apoptotic response are phase-shifted relative to the rhythm of mutagenic stress. The accumulating mutations would lead to accelerated aging, genome instability and neoplasia. The proposed model delineates areas of research with potentially profound implications for carcinogenesis.
Shadan
Farhad F
FF
The Scripps Research Institute and Scripps Clinic, La Jolla, CA 92037, USA. ffshadan@yahoo.com
D000375:Aging; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D002940:Circadian Rhythm; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D004261:DNA Replication; D016678:Genome; D006801:Humans; D008954:Models, Biological; D009153:Mutagens; D009154:Mutation; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D009153:Mutagens; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA