Timeless in animal circadian clocks and beyond

TIMELESS (TIM) was first identified as a molecular cog in the Drosophila circadian clock. Almost three decades of investigations have resulted in an insightful model describing the critical role of Drosophila TIM (dTIM) in circadian timekeeping in insects, including its function in mediating light entrainment and temperature compensation of the molecular clock. Furthermore, exciting discoveries on its sequence polymorphism and thermosensitive alternative RNA splicing have also established its role in regulating seasonal biology. Although mammalian TIM (mTIM), its mammalian paralog, was first identified as a potential circadian clock component in 1990s due to sequence similarity to dTIM, its role in clock regulation has been more controversial. Mammalian TIM has now been characterized as a DNA replication fork component and has been shown to promote fork progression and participate in cell cycle checkpoint signaling in response to DNA damage. Despite defective circadian rhythms displayed by mtim mutants, it remains controversial whether the regulation of circadian clocks by mTIM is direct, especially given the interconnection between the cell cycle and circadian clocks. In this review, we provide a historical perspective on the identification of animal tim genes, summarize the roles of TIM proteins in biological timing and genomic stability, and draw parallels between dTIM and mTIM despite apparent functional divergence.