InterPro domain: IPR006906

This entry represents the N-terminal domain of the Timeless protein.

The timeless gene in Drosophila melanogasteris involved in circadian rhythm control [ 1 ]. Drosophila contains two paralogs, dTIM and dTIM2, acting in clock/photoreception and chromosome integrity/photoreception respectively. The mammalian TIMELESS (TIM) protein, originally identified based on its similarity to Drosophila dTIM, interacts with the clock proteins dCRY and dPER and is essential for circadian rhythm generation and photo-entrainment in the fly [ 2 ]. However, phylogenetic sequence analysis has demonstrated that dTIM2 is likely to be the orthologue of mammalian TIM and other widely conserved TIM-like proteins in eukaryotes [ 3 ]. These proteins include Saccharomyces cerevisiae Tof1, Schizosaccharomyces pombe Swi1, and Caenorhabditis elegans TIM. These proteins are not involved in the core clock mechanism, but instead play important roles in chromosome integrity, efficient cell growth and/or development [ 4 , 5 ], with the exception of dTIM-2, that has an additional function in retinal photoreception [ 6 ].

Saccharomyces cerevisiae Tof1 is a subunit of a replication-pausing checkpoint complex (Tof1-Mrc1-Csm3) that acts at the stalled replication fork to promote sister chromatid cohesion after DNA damage, facilitating gap repair of damaged DNA [ 6 , 7 ]. Schizosaccharomyces pombe Swi1 and Swi3 form the fork protection complex that coordinates leading- and lagging-strand synthesis and stabilizes stalled replication forks [ 8 ].

In humans timeless forms a stable complex with its partner protein Tipin. The Timeless-Tipin complex has been reported to travel along with the replication fork during unperturbed DNA replication. Moreover, the Timeless-Tipin-Claspin complex contributes to full activation of the ATR-Chk1 signaling pathway through the recruitment of Chk1 to arrested replication forks for sufficient ATR-mediated phosphorylation. It also interacts with PARP-1, and this interaction is required for efficient homologous recombination repair [ 9 ].

1. Flies, clocks and evolution. Philos. Trans. R. Soc. Lond., B, Biol. Sci. 356, 1769-78
2. Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science 285, 553-6
3. A second timeless gene in Drosophila shares greater sequence similarity with mammalian tim. Curr Biol 10, R512-3
4. Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PLoS One 8, e56623
5. Crystal structure and interactions of the Tof1-Csm3 (Timeless-Tipin) fork protection complex. Nucleic Acids Res 48, 6996-7004
6. S-phase checkpoint proteins Tof1 and Mrc1 form a stable replication-pausing complex. Nature 424, 1078-83
7. Csm3, Tof1, and Mrc1 form a heterotrimeric mediator complex that associates with DNA replication forks. J Biol Chem 284, 34355-65
8. Swi1 and Swi3 are components of a replication fork protection complex in fission yeast. Mol. Cell. Biol. 24, 8342-55
9. Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair. Mol. Cell 60, 163-76