Timeless (TIM) was initially identified as a component in the Drosophila circadian clock. In insects, Drosophila TIM (dTIM) is crucial for circadian timekeeping, mediating light entrainment and temperature compensation of the molecular clock, and also regulates seasonal biology through sequence polymorphism and thermosensitive alternative RNA splicing [1]. Although mammalian TIM (mTIM) was first thought to be a circadian clock component due to sequence similarity to dTIM, its role in clock regulation is controversial. Currently, 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 protein protects replication forks from stalling at difficult-to-replicate regions like telomeres and is involved in DNA damage response, including checkpoint signaling and DNA repair [2,3]. Loss of TIM causes severe replication stress, while its overexpression is common in various cancers, conferring protection from DNA damage and chemotherapy resistance [2]. In Fusobacterium nucleatum-infected intestinal epithelial cells, the miR-129-2-3p/TIMELESS axis induces DNA damage, activates the ATM/ATR/p53 pathway, promotes cellular senescence, and exacerbates experimental colitis [4].

In conclusion, Timeless plays diverse and important biological functions. In animals, it has roles in circadian clocks and seasonal biology. In mammals, it is crucial for DNA replication fork integrity and genome stability. Its loss-of-function can lead to replication stress, and its abnormal expression is associated with cancer and colitis, highlighting its significance in understanding these disease mechanisms.