Timeless (TIM) was initially identified as a key component in the Drosophila circadian clock [1]. In insects, Drosophila TIM (dTIM) plays a critical role in circadian timekeeping, mediating light entrainment and temperature compensation of the molecular clock, and also has a role in regulating seasonal biology [1]. In mammals, mammalian TIM (mTIM) was initially thought to be a potential circadian clock component due to sequence similarity to dTIM, but its role in clock regulation is controversial [1]. Now, mTIM is characterized as a DNA replication fork component, promoting fork progression and participating in cell cycle checkpoint signaling in response to DNA damage [1].

TIM is part of the fork protection complex (FPC) in DNA replication. Loss of TIM results in impaired fork progression, elevated fork stalling and breakage, and a defect in replication checkpoint activation [2]. TIM also protects replication forks from stalling at difficult-to-replicate regions and is involved in DNA damage response, including checkpoint signaling, protection of stalled replication forks and DNA repair [3]. In fission yeast, a Timeless-related protein Swi1 is required for proper replication of repeat DNA sequences at telomeres [4]. In ulcerative colitis, exosomal-miR-129-2-3p from Fusobacterium nucleatum-infected intestinal epithelial cells can induce DNA damage via the miR-129-2-3p/TIMELESS axis, promoting cellular senescence and colonic inflammation [5].

In conclusion, Timeless has diverse functions. In animals, it is involved in circadian rhythms in insects and DNA replication and genome stability in mammals. Loss-of-function studies in various models, including yeast and in the context of human diseases like ulcerative colitis, have revealed its importance in maintaining genomic integrity and in disease-related cellular processes such as cellular senescence and inflammation [1,2,3,4,5].