ArticlePloS one2013
Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock.
Article in PloS one, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers, 1 of them a synthesis that pooled it.
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Who cites it
43 citing papers in PubMed, 1 synthesis or guideline pooled it, 73 citations in OpenAlex.
- Genetic variation of clock genes and cancer risk: a field synopsis and meta-analysis.Oncotarget · 2017Pooled it
- General intelligence is associated with subclinical inflammation in Nepalese children: A population-based plasma proteomics study.Brain, behavior, and immunity · 2016Trial
- Chemical biology approaches to study and target circadian clocks and their components.FEBS letters · 2026Review
- Hepatocellular Carcinoma Around the Clock.Current oncology (Toronto, Ont.) · 2026Review
- History of exposure to copper influences transgenerational gene expression responses inEpigenetics · 2024Article
- Day-night gene expression reveals circadian geneProceedings. Biological sciences · 2024Article
- Differential Expression of Circadian Clock Genes in the Bovine Neuroendocrine Adrenal System.Genes · 2023Article
- Keratinocytes Exposed to Blue or Red Light: Proteomic Characterization Showed Cytoplasmic Thioredoxin Reductase 1 and Aldo-Keto Reductase Family 1 Member C3 Triggered Expression.International journal of molecular sciences · 2023Article
- Article
- Circadian protein TIMELESS regulates synaptic function and memory by modulating cAMP signaling.Cell reports · 2023Article
- Circadian Rhythm Dysregulation and Leukemia Development: The Role of Clock Genes as Promising Biomarkers.International journal of molecular sciences · 2022Review
- Circadian Rhythm Sleep Disorders: Genetics, Mechanisms, and Adverse Effects on Health.Frontiers in genetics · 2022Review
- The Fork Protection Complex: A Regulatory Hub at the Head of the Replisome.Sub-cellular biochemistry · 2022Article
- High Expression of TIMELESS Predicts Poor Prognosis: A Potential Therapeutic Target for Skin Cutaneous Melanoma.Frontiers in surgery · 2022Article
- Phosphatase of Regenerating Liver-1 Selectively Times Circadian Behavior in Darkness via Function in PDF Neurons and Dephosphorylation of TIMELESS.Current biology : CB · 2021Article
- Temporal Proteomic Profiling of SH-SY5Y Differentiation with Retinoic Acid Using FAIMS and Real-Time Searching.Journal of proteome research · 2021Article
- The Lineage Before Time: Circadian and Nonclassical Clock Influences on Development.Annual review of cell and developmental biology · 2020Review
- Cancer, hear my battle CRY.Journal of pineal research · 2020Review
- Crystal structure and interactions of the Tof1-Csm3 (Timeless-Tipin) fork protection complex.Nucleic acids research · 2020Article
- Molecular mechanisms and physiological importance of circadian rhythms.Nature reviews. Molecular cell biology · 2020Review
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The transcription/translation feedback loop-based molecular oscillator underlying the generation of circadian gene expression is preserved in almost all organisms. Interestingly, the animal circadian clock proteins CRYPTOCHROME (CRY), PERIOD (PER) and TIMELESS (TIM) are strongly conserved at the amino acid level through evolution. Within this evolutionary frame, TIM represents a fascinating puzzle. While Drosophila contains two paralogs, dTIM and dTIM2, acting in clock/photoreception and chromosome integrity/photoreception respectively, mammals contain only one TIM homolog. Whereas TIM has been shown to regulate replication termination and cell cycle progression, its functional link to the circadian clock is under debate. Here we show that RNAi-mediated knockdown of TIM in NIH3T3 and U2OS cells shortens the period by 1 hour and diminishes DNA damage-dependent phase advancing. Furthermore, we reveal that the N-terminus of TIM is sufficient for interaction with CRY1 and CHK1 as well for homodimerization, and the C-terminus is necessary for nuclear localization. Interestingly, the long TIM isoform (l-TIM), but not the short (s-TIM), interacts with CRY1 and both proteins can reciprocally regulate their nuclear translocation in transiently transfected COS7 cells. Finally, we demonstrate that co-expression of PER2 abolishes the formation of the TIM/CRY1 complex through affinity binding competition to the C-terminal tail of CRY1. Notably, the presence of the latter protein region evolutionarily and structurally distinguishes mammalian from insect CRYs. We propose that the dynamic interaction between these three proteins could represent a post-translational aspect of the mammalian circadian clock that is important for its pace and adaption to external stimuli, such as DNA damage and/or light.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.