Timeless (gene)
In 1994, timeless was discovered through forward genetic screening performed by Jeffery L. Price while working in the lab of Michael W.
[2][3] The tim01 mutation caused arrhythmic behavior, defined by the lack of ability to establish proper circadian rhythms.
The length of the coding region of the Drosophila timeless gene is 4029 base pairs, from which a 1398 amino acid protein is transcribed.
There is also a region of unknown function near the N-terminus of the TIM protein that contains a 32 amino acid sequence that, when deleted, causes arrhythmic behavior in the fly.
[3] It acts as part of an autoregulatory feedback loop in conjunction with the period (per) gene product as noted in collaborative studies performed by the labs of Michael W. Young and Amita Sehgal.
[8][10][11] Experiments done jointly by the Weitz, Young, and Sehgal labs using yeast 2-hybrid proved that TIM directly binds with PER.
This process leads to the rapid degradation of the TIM protein, allowing organisms to entrain at dawn to environmental cycles.
[8] In some cell types, the photoreceptor protein cryptochrome (CRY) physically associates with TIM and helps regulate light-dependent degradation.
[17] In Drosophila, the negative regulator PER, from the PER/TIM complex, is eventually degraded by a casein kinase-mediated phosphorylation cycle, allowing fluctuations in gene expression according to environmental cues.
In wild type Gryllus bimaculatus, tim mRNA shows rhythmic expression in both LD and DD (dark-dark cycles) similar to that of per, peaking during the subjective night.
These results suggest that in the cricket, tim plays some role in fine-tuning of the free-running period but may not be essential for oscillation of the circadian clock.
Recent work on the mammalian timeless (mTim) in mice has suggested that the gene may not play the same essential role in mammals as in Drosophila as a necessary function of the circadian clock.
[24] The human timeless protein (hTIM) has been shown to be required for the production of electrical oscillations output by the suprachiasmatic nucleus (SCN), the major clock governing all tissue-specific circadian rhythms of the body.
[23] With respect to the G2/M checkpoint, hTIM binds to the ATRIP subunit on ATR – a protein kinase sensitive to DNA damage.
[23] This process serves as an important control to stop the proliferation of cells with DNA damage prior to mitotic division.
It was found that elevated expression of Timeless was significantly associated with more advanced tumor stage and poorer breast cancer prognosis.
[29] Similarity in gene expression signatures has allowed for TIMELESS to be identified as Kinase Suppressor of Ras-1 (KSR1)-like and a potential target required for cancer cell survival.
