Light-Dependent Sequestration of TIMELESS by CRYPTOCHROME

Ceriani, M. Fernanda; Darlington, Thomas K.; Staknis, David; Más, Paloma Díaz; Petti, Allegra A.; Weitz, Charles J.; Kay, Steve A.

doi:10.1126/science.285.5427.553

Cited by 516 publications

(400 citation statements)

References 32 publications

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“…An attractive possibility is that the higher mir-276a levels during the daytime are caused by light-mediated up-regulation of CF2 activity. This pathway might complement the more traditional pathways that also lower TIM levels in response to light (24,28,(32)(33)(34).…”

Section: Discussionmentioning

confidence: 99%

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Xiao

Rosbash

2016

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms in metazoan eukaryotes are controlled by an endogenous molecular clock. It functions in many locations, including subsets of brain neurons (clock neurons) within the central nervous system. Although the molecular clock relies on transcription/translation feedback loops, posttranscriptional regulation also plays an important role. Here, we show that the abundant Drosophila melanogaster microRNA mir-276a regulates molecular and behavioral rhythms by inhibiting expression of the important clock gene timeless (tim). Misregulation of mir-276a in clock neurons alters tim expression and increases arrhythmicity under standard constant darkness (DD) conditions. mir-276a expression itself appears to be light-regulated because its levels oscillate under 24-h light-dark (LD) cycles but not in DD. mir-276a is regulated by the transcription activator Chorion factor 2 in flies and in tissue-culture cells. Evidence from flies mutated using the clustered, regularly interspaced, short palindromic repeats (CRISPR) tool shows that mir-276a inhibits tim expression: Deleting the mir276a-binding site in the tim 3′ UTR causes elevated levels of TIM and ∼50% arrhythmicity. We suggest that this pathway contributes to the more robust rhythms observed under light/dark LD conditions than under DD conditions. microRNA | circadian rhythms | light regulation | CRISPR

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Section: Discussionmentioning

confidence: 99%

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Xiao

Rosbash

2016

Proc. Natl. Acad. Sci. U.S.A.

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“…The Timeless (TIM) protein interacts with clock proteins and is essential for generation of a circadian rhythm in flies (3). In addition, phylogenetic sequence analysis revealed the presence of a paralogue in D. melanogaster (4), which is not involved in the core clock machinery, but is important for the maintenance of chromosome integrity, growth control, and development.…”

Section: Introductionmentioning

confidence: 99%

Protumorigenic role of Timeless in hepatocellular carcinoma

Elgohary

Pellegrino

Neumann

et al. 2014

International Journal of Oncology

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Abstract. The mammalian timeless (TIM) protein interacts with proteins of the endogenous clock and essentially contributes to the circadian rhythm. In addition, TIM is involved in maintenance of chromosome integrity, growth control and development. Thus, we hypothesized that TIM may exert a potential protumorigenic function in human hepatocarcinogenesis. TIM was overexpressed in a subset of human HCCs both at the mRNA and the protein level. siRNA-mediated knockdown of TIM reduced cell viability due to the induction of apoptosis and G2 arrest. The latter was mediated via CHEK2 phosphorylation. In addition, siRNA-treated cells showed a significantly reduced migratory capacity and reduced expression levels of various proteins. Mechanistically, TIM directly interacts with the eukaryotic elongation factor 1A2 (EEF1A2), which binds to actin filaments to promote tumor cell migration. siRNA-mediated knockdown of TIM reduced EEF1A2 protein levels thereby affecting ribosomal protein biosynthesis. Thus, overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2. IntroductionMany biological processes show a circadian rhythm, which is controlled by an endogenous clock that synchronizes with day and night phases of the solar day. The periodical rhythm is generated by a molecular oscillator located in the suprachiasmatic nuclei of the hypothalamus, which controls peripheral oscillators in virtually any other cell (1). The circadian clock is organized through a complex network of transcriptiontranslational feedback loops that drive rhythmic expression patterns of core clock components in mammals (2).The Timeless (TIM) protein interacts with clock proteins and is essential for generation of a circadian rhythm in flies (3). In addition, phylogenetic sequence analysis revealed the presence of a paralogue in D. melanogaster (4), which is not involved in the core clock machinery, but is important for the maintenance of chromosome integrity, growth control, and development. In contrast, a single TIM gene has been identified in mammals, which acquired all of these functions as indicated by its role in DNA damage response, replication, and circadian rhythm (5-9). Consistently, TIM knockout resulted in embryonic lethality in mice (10). In addition, TIM and other clock genes have been linked to human carcinogenesis (11)(12)(13)(14). Using integrative molecular profiling we have recently identified that inactivation of Period homolog 3, a component of the clock machinery, occurs in human HCC indicating that dysregulation of this regulatory network may contribute to hepatocarcinogenesis (15).The eukaryotic elongation factor 1-α (EEF1A), a member of the G protein family, represents one of the four subunits that constitute the eukaryotic elongation factor 1 (16). In humans,

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“…Thus, PER and TIM may not enter the nucleus together, as also suggested by in vivo studies where PER was detected in the nucleus before TIM [45]. Foci of transfected CRY protein were previously observed in the cytoplasm of S2 cells, and these aggregations were dependent on PER, TIM and light [46]. Care has to be taken with interpreting data from S2 cells, as equivalent foci have not been identified in vivo and also since there are contradictory conclusions in the literature between the findings from S2 cells and arrhythmic pacemaker neurons [47,48].…”

Section: Reconstructing the Clockmentioning

confidence: 64%

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

Collins

Blau

2007

Pflugers Arch - Eur J Physiol

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"Even a stopped clock tells the right time twice a day, and for once I'm inclined to believe Withnail is right. We are indeed drifting into the arena of the unwell... What we need is harmony. Fresh air. Stuff like that." Bruce Robinson (1986, ref. 1). Although a stopped Drosophila clock probably does not tell the right time even once a day, recent findings have demonstrated that accurate circadian time-keeping is dependent on harmony between groups of clock neurons within the brain. Furthermore, when harmony between the environment and the endogenous clock is lost, as during jet lag, we definitely feel unwell. In this review, we provide an overview of the current understanding of circadian rhythms in Drosophila, focussing on recent discoveries that demonstrate how approximately 100 neurons within the Drosophila brain control the behaviour of the whole fly, and how these rhythms respond to the environment.

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Light-Dependent Sequestration of TIMELESS by CRYPTOCHROME

Cited by 516 publications

References 32 publications

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression

Protumorigenic role of Timeless in hepatocellular carcinoma

Even a stopped clock tells the right time twice a day: circadian timekeeping in Drosophila

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