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Plays an important role in the control of DNA replication, maintenance of replication fork stability, maintenance of genome stability throughout normal DNA replication, DNA repair and in the regulation of the circadian clock. Required to stabilize replication forks during DNA replication by forming a complex with TIPIN: this complex regulates DNA replication processes under both normal and stress conditions, stabilizes replication forks and influences both CHEK1 phosphorylation and the intra-S phase checkpoint in response to genotoxic stress. TIMELESS promotes TIPIN nuclear localization. Involved in cell survival after DNA damage or replication stress by promoting DNA repair. In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1. May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light. Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock. Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.
基因功能參考文獻(xiàn):
we suggest that disturbances in timeless expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells and promoting carcinogenesis. PMID: 30249891
TIM rs2291738 was associated with chronotype dimensions PMID: 28708003
Inhibition of MYC significantly blocked the effects of TIM on CSC population, cell invasion and anchor-independent cell growth. TIM plays an important role in promoting breast cancer progression and may represent a novel therapeutic target for breast cancer. PMID: 28464854
Stable ectopic overexpression of TIMELESS in nasopharyngeal carcinoma cell lines conferred resistance to cisplatin-induced apoptosis in vitro and in vivo, promoted an epithelial-to-mesenchymal transition phenotype, and activated the Wnt/beta-catenin pathway and downstream gene transcription. PMID: 28583847
the 1.85 A crystal structure of a large N-terminal segment of human Timeless, spanning amino acids 1-463, is presented and this region of human Timeless harbours a partial binding site for Tipin. PMID: 28334766
results provide the first evidence that TIM is required for the correct chromatin association of the CMG complex to allow efficient DNA replication. PMID: 27587400
Our results show that TIMELESS overexpression correlates with pelvic lymph node metastasis, lymphovascular space involvement, as well as unfavorable OS and DFS in human cervical cancer. Therefore, TIMELESS expression may be a potential prognostic biomarker for cervical cancer patients PMID: 27909716
TIMELESS mutants unable to bind PARP1. TIMELESS silencing significantly impairs DNA double-strand break repair. PMID: 26456830
Data reports the crystal structure of Timeless-PARP-1 complex and provides evidence that Timeless is recruited to sites of DNA damage through PARP-1 to mediate homologous recombination repair of DNA double-strand breaks. PMID: 26344098
overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2. PMID: 25405317
TIMELESS and RORA genes may confer susceptibility to bipolar disorders and impact on circadian phenotypes PMID: 24716566
The results of this study suggest that the TIMELESS gene may be associated with the lithium prophylactic response in bipolar illness. PMID: 24636202
TIMELESS is frequently overexpressed in various types of tumor tissues, and elevated TIMELESS expression is associated with advanced tumor stage and poorer breast cancer prognosis. PMID: 24161199
Data indicate that RNAi-mediated knockdown of TIMELESS (TIM) in NIH3T3 and U2OS cells shortens the period by 1 hour and diminishes DNA damage-dependent phase advancing. PMID: 23418588
TIMELESS has a distinct contribution to suppression of chromosomal instability that is independent of its heterodimeric partner, TIPIN. PMID: 23255133
Tim-Tipin complex (or Tim alone) is able to associate with DNA polymerase epsilon bound to a 40-/80-mer DNA ligand. PMID: 23511638
All lung cancer specimens but no matched normal lung tissues were positive for TIM expression. PMID: 23173913
Kaposi's Sarcoma-associated herpesvirus episome maintenance requires Tim-assisted replication fork protection at the viral terminal repeats. PMID: 23325691
observed a significant association between stage II, III, and IV breast cancers and TIMELESS promoter hypomethylation in peripheral blood lymphocytes in 80 breast cancer cases and 80 age-matched controls PMID: 22006848
Timeless functions together with TRF1 to prevent fork collapse at telomere repeat DNA and ensure stable maintenance of telomere length and integrity. PMID: 22672906
Timeless has a function in SCC that is independent of the Tim-Tipin complex, even though the abundance of Timeless is reduced when Tipin is targeted for depletion. PMID: 21508667
Tim coordinates mitotic kinase activation with termination of DNA replication. PMID: 21573113
These findings demonstrate that Tim is essential for sustaining the episomal forms of EBV DNA in latently infected cells. PMID: 21490103
the interaction between dPERIOD and dCLOCK is TIM-dependent and modulated by light, revealing a novel and unanticipated in vivo role for TIM in circadian transcription PMID: 20980603
Data show significant association between TIMELESS variants and depression with fatigue in females, and association to depression with early morning awakening in males. PMID: 20174623
The results suggest that Timeless-Tipin functions as a replication fork stabilizer that couples DNA replication with sister chromatid cohesion established at replication forks. PMID: 20124417
TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control PMID: 19996108
Down-regulation of Timeless in human cells seriously compromises replication and intra-S checkpoints, indicating an intimate connection between the circadian cycle and the DNA damage checkpoints that is in part mediated by the Timeless protein. PMID: 15798197
Tipin is a checkpoint mediator that cooperates with Tim and may regulate the nuclear relocation of Claspin in response to replication checkpoint PMID: 17102137
observation explains the similar checkpoint phenotypes observed in both Tipin- and Timeless-depleted cells PMID: 17116885
TIM and Tipin are functional orthologs of their replisome-associated yeast counterparts capable of coordinating replication with genotoxic stress responses, and distinguishes mammalian TIM from the circadian-specific paralogs. PMID: 17141802
These findings indicate that the Tim-Tipin complex mediates the UV-induced intra-S checkpoint, Tim is needed to maintain DNA replication fork movement, Tipin interacts with RPA on DNA. PMID: 17296725
HRPAP20 and TIMELESS as promising markers of tamoxifen resistance in women with ER alpha-positive breast tumors. PMID: 17909269
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亞細(xì)胞定位:
Nucleus. Chromosome.
蛋白家族:
Timeless family
組織特異性:
Expressed in all tissues examined including brain, heart, lung, liver, skeletal muscle, kidney, placenta, pancreas, spleen, thymus and testis. Highest levels of expression in placenta, pancreas, thymus and testis.