Department of Entomology and Nematology, College of Agricultural and Environmental Sciences, University of California Davis, CA, USA.
FEBS J. 2022 Nov;289(21):6559-6575. doi: 10.1111/febs.16253. Epub 2021 Nov 18.
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.
TIM 最初是在果蝇的生物钟中被鉴定为分子钟的一个组成部分。近三十年的研究已经形成了一个有见地的模型，描述了果蝇 TIM（dTIM）在昆虫生物钟中的关键作用，包括其在介导光适应和温度补偿分子钟方面的功能。此外，关于其序列多态性和热敏性可变剪接的令人兴奋的发现，也确立了其在调节季节性生物学中的作用。尽管哺乳动物 TIM（mTIM）作为 dTIM 的哺乳动物同源物，由于与 dTIM 的序列相似性，在 20 世纪 90 年代首先被鉴定为潜在的生物钟成分，但它在时钟调节中的作用一直存在争议。哺乳动物 TIM 现在被描述为 DNA 复制叉的组成部分，并已被证明可以促进叉的进展，并在响应 DNA 损伤时参与细胞周期检查点信号。尽管 mtim 突变体表现出缺陷的昼夜节律，但 mTIM 是否直接调节生物钟仍然存在争议，尤其是考虑到细胞周期和生物钟之间的相互联系。在这篇综述中，我们提供了动物 tim 基因鉴定的历史背景，总结了 TIM 蛋白在生物计时和基因组稳定性中的作用，并在明显的功能分歧中，比较了 dTIM 和 mTIM。
