Affinage

TIMELESS

Protein timeless homolog · UniProt Q9UNS1

Length
1208 aa
Mass
138.7 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TIMELESS (TIM) is a dual-function scaffold protein that operates in two distinct biological arenas: the circadian clock and DNA replication/genome maintenance. In Drosophila, TIM is a core clock component whose loss abolishes behavioral and molecular rhythms and disrupts cycling of period (per) RNA (PMID:8128246). TIM heterodimerizes with PER through a heterotypic interaction in which a restricted TIM segment engages the PER PAS domain — TIM itself lacks a PAS domain (PMID:7481773, PMID:7481771) — and this cytoplasmic PER/TIM assembly is required for nuclear translocation of both partners and for negative feedback onto CLOCK/CYCLE-driven transcription (PMID:8128247, PMID:8938123, PMID:10839368). TIM abundance and activity are gated environmentally and biochemically: light triggers rapid posttranscriptional TIM degradation to reset the clock (PMID:8625406, PMID:8596937), a sequential GSK-3/CK2 phosphorylation cascade times nuclear accumulation of the PER/TIM repressor (PMID:18815259, PMID:27346344), and phosphorylated versus hypophosphorylated TIM is targeted for ubiquitylation by SLIMB(SCF) and CULLIN-3 acting cooperatively (PMID:12432393, PMID:22879814, PMID:29791839). Light-dependent inhibition is executed by CRYPTOCHROME, which directly binds TIM; cryo-EM of the CRY–TIM complex shows CRY engaging an N-terminal armadillo-repeat core and a C-terminal TIM helix, with the TIM N-terminus displacing the autoinhibitory CRY C-terminal tail released upon photoactivation (PMID:10417378, PMID:37100907). In mammals, TIMELESS functions principally as a replication fork protection complex scaffold: it forms a mutually stabilizing complex with TIPIN via N-terminal segments (PMID:12875843, PMID:17116885, PMID:17102137), associates with the replisome and binds RPA34, and is required for efficient replication, intra-S and ATR-CHK1/ATM-CHK2 checkpoint signaling (PMID:15798197, PMID:17141802, PMID:17102137, PMID:19996108). Through these activities TIMELESS promotes sister chromatid cohesion and cohesin chromatin loading (PMID:20124417, PMID:21508667), stimulates the DDX11 helicase and binds G-quadruplex DNA via a C-terminal domain to maintain processive replication through G4 structures (PMID:26503245, PMID:32705708), protects stalled/reversed forks from MRE11-dependent degradation in concert with SDE2 (PMID:33127907), and supports CUL-2-dependent CMG helicase ubiquitylation during replication termination (PMID:34269473). TIMELESS additionally binds PARP-1 through a dedicated PARP-binding domain to promote homologous recombination and double-strand break repair (PMID:26344098, PMID:26456830), and retains conserved clock roles in mammals, where a human TIMELESS mutation that impairs nuclear accumulation and CRY2 binding causes familial advanced sleep phase (PMID:31138685).

Mechanistic history

Synthesis pass · year-by-year structured walk · 26 steps
  1. 1994 High

    Established TIMELESS as a genuine core clock gene by showing its loss collapses both behavioral rhythms and the molecular oscillation of per RNA, defining a second clock locus acting on per.

    Evidence tim loss-of-function mutants with behavioral and RNA analyses in Drosophila

    PMID:8128246

    Open questions at the time
    • Molecular identity and biochemical function of TIM unknown at this stage
    • Did not reveal whether the effect on per was transcriptional or posttranscriptional
  2. 1994 High

    Answered how TIM controls PER by showing TIM is required for PER nuclear localization, placing TIM as a regulator of PER subcellular trafficking.

    Evidence Immunocytochemistry of PER in tim mutant vs wild-type brains plus PER fusion localization

    PMID:8128247

    Open questions at the time
    • Whether TIM acts directly on PER or indirectly was not yet resolved
    • PER domain mapping was incomplete
  3. 1995 High

    Demonstrated that TIM and PER physically interact via a heterotypic association (TIM binds the PER PAS domain) and that TIM lacks a PAS domain, defining the molecular basis of clock heterodimer assembly.

    Evidence Yeast two-hybrid, in vitro binding, perL temperature-sensitive binding assays, and positional cloning/sequencing in Drosophila

    PMID:7481771 PMID:7481773

    Open questions at the time
    • Atomic structure of the interaction not determined
    • How binding controls nuclear entry not yet mechanistically defined
  4. 1995 High

    Showed tim RNA cycles in autoregulatory feedback and that TIM exerts a posttranscriptional effect on PER abundance and phosphorylation, establishing the negative-feedback architecture of the oscillator.

    Evidence Northern blots and Western analyses across LD/DD with genetic epistasis in Drosophila

    PMID:7481772 PMID:7664743

    Open questions at the time
    • Kinases and ligases producing the phosphorylation/abundance changes not yet identified
  5. 1996 High

    Identified TIM as the light-sensitive node of the clock by showing TIM protein oscillates and is rapidly degraded by light in a manner coupled to behavioral phase shifts, and that cytoplasmic PER/TIM heterodimer assembly is required for nuclear import of either protein.

    Evidence Immunostaining/light-pulse experiments in Drosophila heads, phase-response curves, and S2 cell co-expression with domain mapping

    PMID:8596937 PMID:8625406 PMID:8938123

    Open questions at the time
    • Photoreceptor and degradation machinery mediating light response not yet identified
    • Nuclear import machinery not defined
  6. 1999 High

    Defined the light input mechanism by showing CRYPTOCHROME directly and light-dependently binds TIM to block PER/TIM function, separating CRY-mediated inactivation from TIM degradation.

    Evidence Light-dependent yeast two-hybrid, co-IP, and subcellular localization in Drosophila

    PMID:10417378

    Open questions at the time
    • Structural basis of CRY-TIM engagement unknown at this stage
    • How CRY binding triggers degradation not resolved
  7. 2002 High

    Identified the ubiquitin ligase logic of clock protein turnover by showing the F-box protein SLIMB targets phosphorylated PER and TIM for degradation, linking phosphorylation to timed proteolysis.

    Evidence slimb mutant genetics with Western analysis of PER/TIM levels and phosphorylation in Drosophila

    PMID:12432393

    Open questions at the time
    • Which kinases prime the phosphodegron not yet defined
    • Whether additional ligases act on TIM unknown
  8. 2003 Medium

    Extended TIM's clock role to mammals and revealed a second, essential function: mTIM oscillates in the SCN and binds PERs, yet is also required for embryonic viability, hinting at a non-clock essential role.

    Evidence Conditional SCN knockdown, co-IP from SCN, and mouse knockout in mammals

    PMID:14564007

    Open questions at the time
    • Did not define the essential developmental function
    • Conditional knockdown is single-lab
  9. 2003 Medium

    Discovered TIPIN as a dedicated TIM partner that disrupts TIM self-multimerization and is reciprocally trafficked, establishing the TIM-TIPIN heterodimer as the functional unit.

    Evidence Yeast two-hybrid, in vitro binding, co-IP and immunofluorescence in cultured cells

    PMID:12875843

    Open questions at the time
    • Cellular pathway of the TIM-TIPIN complex not yet established
    • Single-lab interaction data
  10. 2005 High

    Bridged TIMELESS to genome maintenance by showing it binds CHK1 and the ATR-ATRIP complex (and CRY2), and that its loss cripples replication and intra-S checkpoints, defining a checkpoint scaffold role.

    Evidence Reciprocal co-IP and siRNA knockdown with checkpoint assays in human cells

    PMID:15798197

    Open questions at the time
    • Whether the checkpoint role is direct at forks or via signaling not yet resolved
    • Mechanism of ATR activation unclear
  11. 2006 High

    Localized the TIM-TIPIN complex to the replisome and demonstrated direct RPA34 binding plus mutual TIM-TIPIN stabilization, defining the fork-protection complex and its role in CHK1 activation and Claspin nuclear accumulation.

    Evidence Co-IP with replisome components, SPR direct binding to RPA34, chromatin fractionation, domain mapping and knockdown in human cells

    PMID:17102137 PMID:17116885 PMID:17141802

    Open questions at the time
    • How the complex couples fork progression to checkpoint signaling mechanistically not fully resolved
  12. 2009 Medium

    Broadened TIM's checkpoint role beyond ATR by showing it is required for ATM-dependent CHK2 activation and the G2/M checkpoint, and that its loss sensitizes cancer cells to doxorubicin.

    Evidence siRNA knockdown with CHK2 phosphorylation, cell-cycle and viability assays in human cancer cells

    PMID:19996108

    Open questions at the time
    • Direct vs indirect role in ATM signaling not established
    • Single-lab
  13. 2010 High

    Linked the fork-protection complex to sister chromatid cohesion by showing Timeless loads cohesin during S phase, associates with cohesin and the ChlR1 helicase, and is required to prevent chromosome fragmentation.

    Evidence ChIP at origins, co-IP with cohesin/ChlR1, cohesion and chromosome-fragmentation assays in human cells

    PMID:20124417

    Open questions at the time
    • Mechanism coupling replication to cohesin loading not fully defined
  14. 2011 Medium

    Resolved that Timeless has a TIPIN- and CHK1-independent function in sister chromatid cohesion, distinguishing its cohesion role from its checkpoint/complex roles.

    Evidence Comparative siRNA knockdown of Timeless, Tipin, Claspin, Chk1, ATR with SCC quantification in human fibroblasts

    PMID:21508667

    Open questions at the time
    • Molecular mechanism of the TIPIN-independent cohesion function unknown
    • Single-lab
  15. 2011 Medium

    Demonstrated TIM's importance for viral episome maintenance, showing Tim/Tipin act at EBV and KSHV origins during S phase to support replication and prevent recombination/DSB accumulation.

    Evidence ChIP at viral origins, knockdown, Southern blot and 2D-gel replication-intermediate analysis in infected cells

    PMID:21490103 PMID:23325691

    Open questions at the time
    • Whether viral and cellular fork-protection functions are mechanistically identical not established
    • Single-lab studies
  16. 2012 Medium

    Showed TIM supports telomere replication via Shelterin (TRF1/TRF2) association, preventing telomere shortening independently of telomerase.

    Evidence Telomere length assays, co-IP with TRF1/TRF2 and in vitro telomere replication in human cells

    PMID:22672906

    Open questions at the time
    • Direct vs indirect recruitment to telomeres not resolved
    • Single-lab
  17. 2012 High

    Refined clock proteolysis by showing CULLIN-3 targets hypophosphorylated TIM while SLIMB targets phosphorylated TIM, with the two ligases acting additively, and connected TIM to circadian immune output (phagocytosis).

    Evidence RNAi/dominant-negative CUL-3, co-IP, Western analysis, and phagocytosis/survival assays in Drosophila

    PMID:22253593 PMID:22879814

    Open questions at the time
    • How phosphorylation state switches ligase selectivity mechanistically not defined
    • Immune mechanism inferred but not molecularly resolved
  18. 2013 Medium

    Mapped mammalian TIM domains controlling clock function, showing the N-terminus binds CRY1/CHK1 and mediates homodimerization while the C-terminus drives nuclear localization, with isoform-specific CRY1 binding and PER2 competition.

    Evidence RNAi period measurement, co-IP domain mapping and nuclear translocation assays in mammalian cells

    PMID:23418588

    Open questions at the time
    • Structural basis of domain interactions not resolved
    • Single-lab
  19. 2015 High

    Defined the TIM-PARP-1 interaction as a distinct repair function, providing a crystal structure of the PARP-binding domain and showing PARP-1-dependent recruitment to damage and a requirement for efficient HR/DSB repair.

    Evidence Co-IP, X-ray crystallography of the PAB domain-PARP-1 complex, laser-microirradiation and HR/DSB repair assays in human cells

    PMID:26344098 PMID:26456830

    Open questions at the time
    • How TIM coordinates fork protection and HR repair functions not fully integrated
  20. 2015 High

    Established TIM as a positive regulator of the DDX11 helicase, stimulating unwinding of forked, G-quadruplex and D-loop substrates and acting epistatically in fork progression and recovery.

    Evidence In vitro helicase assays, SPR binding, EMSA, DNA fiber tracks and co-depletion epistasis in HeLa cells

    PMID:26503245

    Open questions at the time
    • Whether DDX11 stimulation requires the full fork-protection complex unknown
    • Single-lab
  21. 2016 High

    Resolved the kinase cascade timing nuclear repressor accumulation, showing GSK-3/SGG phosphorylates PER-bound TIM to prime a CK2 cascade restricted to master pacemaker neurons.

    Evidence In vitro kinase assays, phosphosite mutagenesis, nuclear accumulation and behavioral genetics in Drosophila

    PMID:18815259 PMID:27346344

    Open questions at the time
    • Precise phosphosite hierarchy and link to ligase selectivity not fully mapped
  22. 2018 Medium

    Showed CULLIN-3 and SLIMB cooperatively ubiquitylate TIM and that spliceosomal control (PRP4 kinase/tri-snRNP) of tim alternative splicing rhythmically tunes TIM levels, adding ubiquitylation and splicing layers to clock regulation.

    Evidence In vivo ubiquitin labeling/MS/co-IP and an RNAi/RNA-seq splicing screen in Drosophila

    PMID:29791839 PMID:30516472

    Open questions at the time
    • How splicing rhythm is generated upstream not defined
    • Single-lab studies
  23. 2019 High

    Connected TIM to human disease and to checkpoint-independent fork protection: a TIMELESS FASP mutation impairs nuclear accumulation and CRY2 binding, while Claspin/Timeless overexpression protects forks in cancer cells without altering checkpoint signaling.

    Evidence Human genetics, CRISPR mice, co-IP and MEF period measurement; plus DNA fiber and checkpoint analyses in fibroblasts/cancer cells

    PMID:30796221 PMID:31138685

    Open questions at the time
    • Mechanism of checkpoint-independent fork protection not molecularly resolved
  24. 2020 High

    Defined the molecular basis of TIM's G4 function, identifying a C-terminal G4-binding domain partially redundant with the PARP-binding domain that, together with DDX11, maintains processive replication through G4 structures, and added SDE2 as a stabilizer protecting forks from MRE11.

    Evidence EMSA with G4 DNA, domain mutagenesis, DNA fiber/epistasis with DDX11, plus co-IP and reversed-fork degradation assays in human cells

    PMID:32705708 PMID:33127907

    Open questions at the time
    • How G4 binding is coordinated with helicase recruitment in vivo not fully resolved
  25. 2021 High

    Placed TIM-TIPIN in replication termination by showing it recruits CUL-2(LRR-1) to ubiquitylate the CMG helicase MCM-7 subunit for CDC-48-mediated replisome disassembly, with synthetic lethality on UBXN-3 co-depletion.

    Evidence In vitro CMG ubiquitylation reconstitution and in vivo C. elegans genetics/epistasis

    PMID:34269473

    Open questions at the time
    • Whether mammalian termination uses identical TIM-dependent recruitment not directly shown here
  26. 2023 High

    Provided the structural mechanism of light-dependent clock inactivation, showing by cryo-EM how CRY engages TIM armadillo repeats and how the TIM N-terminus replaces the released CRY autoinhibitory tail, explaining light-sensitivity polymorphisms.

    Evidence Cryo-EM structure of the Drosophila CRY-TIM complex with interface analysis

    PMID:37100907

    Open questions at the time
    • Does not resolve the structure of the mammalian TIM-CRY or TIM-replisome complexes
    • Importin-alpha regulation by phospho-TIM inferred from structure, not directly tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein is partitioned between its circadian clock role and its essential fork-protection/repair role, and whether the two functions share regulatory inputs, remains unresolved.
  • No structural model of the mammalian TIM-TIPIN-replisome complex
  • Regulatory crosstalk between clock and replication functions undefined
  • Mechanism integrating G4 binding, DDX11 stimulation, PARP-1/HR and cohesion roles not unified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0140110 transcription regulator activity 3 GO:0098772 molecular function regulator activity 2 GO:0003677 DNA binding 1
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 2 GO:0005829 cytosol 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-9909396 Circadian clock 4 R-HSA-1640170 Cell Cycle 3 R-HSA-69306 DNA Replication 3 R-HSA-73894 DNA Repair 3
Partners
ATRCHK1CRY (CRY1/CRY2)DDX11PARP-1PERRPA34TIPIN
Complex memberships
CRY-TIM complexPER/TIM clock complexTIMELESS-TIPIN fork protection complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 TIMELESS (TIM) is required for circadian rhythmicity in Drosophila; tim mutation abolishes both eclosion and locomotor activity rhythms and disrupts circadian oscillations of period (per) RNA, establishing TIM as a core clock component that regulates per expression. Genetic loss-of-function (tim mutant flies), behavioral assays, RNA analysis Science High 8128246
1994 TIM is required for nuclear localization of the PERIOD (PER) protein; in tim mutant flies, PER is excluded from nuclei, and a PER domain containing the PAS region and flanking sequences is responsible for this cytoplasmic retention in the absence of TIM. Immunocytochemistry of PER in tim mutant and wild-type Drosophila brains; PER fusion protein localization Science High 8128247
1995 TIM protein physically interacts with PER via a direct heterotypic protein-protein interaction; a restricted segment of TIM binds the PER PAS dimerization domain. The long-period PERL mutation causes a temperature-sensitive defect in TIM binding, correlating with delayed PER nuclear entry. Yeast two-hybrid screen (TIM cloned by PER interaction), in vitro binding assay, temperature-sensitive binding assay with PERL mutant Science High 7481773
1995 tim RNA levels cycle with a circadian rhythm (same phase as per RNA), and these oscillations depend on feedback from PER and TIM proteins themselves, demonstrating autoregulatory feedback control of tim transcription. Cyclic TIM expression controls timing of PER protein accumulation and nuclear localization. Northern blot RNA quantification in wild-type and mutant Drosophila under LD and DD; genetic epistasis using per and tim mutants Science High 7481772
1995 TIM protein positional cloning revealed it encodes a 1389 amino acid protein with no PAS domain, indicating that the PER-TIM interaction requires a heterotypic association. The arrhythmic tim01 allele results from a 64-bp deletion truncating TIM to 749 amino acids. Positional cloning, sequencing, deletion mapping Science High 7481771
1995 In tim mutant flies, PER protein levels are constitutively low and do not cycle; TIM suppresses circadian cycling of PER protein abundance and PER phosphorylation, suggesting TIM has a primary posttranscriptional effect on PER expression. Western blot analysis of PER protein levels and phosphorylation state in tim mutants vs. wild-type The EMBO journal High 7664743
1996 TIM protein levels oscillate with a circadian rhythm, peaking later than TIM RNA by several hours. Nuclear expression of TIM requires PER protein. Light rapidly reduces TIM (but not PER) protein levels posttranscriptionally, establishing TIM as the mediator of light-induced clock resetting. Immunostaining of TIM protein in adult Drosophila heads across circadian cycle; light-pulse experiments; per mutant analysis Cell High 8625406
1996 TIM is rapidly degraded by light exposure, and TIM accumulates rhythmically in nuclei of eyes and pacemaker brain cells. Light-induced phase shifts in TIM protein levels correspond to behavioral phase shifts, coupling the molecular pacemaker to the environment. Immunostaining of TIM protein after light pulses at different times; behavioral phase-response curves Science High 8596937
1996 PER and TIM accumulate in the cytoplasm when independently expressed in Drosophila S2 cells, but translocate to nuclei when coexpressed. Domains within each protein inhibit nuclear localization when monomeric; the sequence blocking PER nuclear accumulation forms a TIM-binding site. Cytoplasmic assembly of PER/TIM heterodimer is required for nuclear transport of either protein. Transfection of Drosophila S2 cells with PER and TIM expression constructs, immunofluorescence, domain-deletion mapping, in vitro protein interaction Neuron High 8938123
1996 The timSL allele of timeless acts as an allele-specific suppressor of perL, restoring temperature compensation and altering the temporal pattern of PERL protein nuclear localization. timSL alters TIM phosphorylation during late night, providing evidence that TIM phosphorylation contributes to the circadian timekeeping mechanism. Genetic suppressor screen, behavioral rhythmicity assays, immunocytochemistry, yeast binding assay, Western blot phosphorylation analysis Neuron Medium 8938124
1998 Human TIMELESS (hTIM) interacts with Drosophila PER and with mouse PER1 and PER2 in vitro. In Drosophila S2 cells, hTIM and dPER interact and translocate to the nucleus. hTIM and mPER1 specifically inhibit CLOCK-BMAL1-induced transactivation of the mPer1 promoter. In vitro binding assay, co-transfection + immunofluorescence in S2 cells, transcriptional reporter assay Neuron High 9856465
1999 Drosophila CRYPTOCHROME (CRY) blocks PER/TIM complex function in a light-dependent manner by directly interacting with TIM. CRY and TIM are part of the same complex, interact in yeast in a light-dependent fashion, and light signals cause PER/TIM/CRY complexes to reside primarily in the nucleus. TIM degradation is uncoupled from abrogation of its function by CRY. Yeast two-hybrid interaction (light-dependent), co-immunoprecipitation, subcellular localization (immunofluorescence) Science High 10417378
1999 TIM positively regulates per mRNA levels through a post-transcriptional mechanism, in addition to its role in negative feedback. Heat-shock induction of TIM in tim loss-of-function flies rapidly initiates a molecular cycle of PER accumulation, revealing both positive and negative autoregulatory roles for TIM. Heat-shock inducible transgene rescue in tim null background; RNA and protein analyses after TIM induction The EMBO journal Medium 9927427
2000 In the absence of TIM (after light-induced TIM degradation), nuclear PER alone can function as a potent negative transcriptional repressor of dCLOCK/CYCLE-mediated per and tim transcription. Constitutively nuclear PER represses dCLOCK/CYCLE transcription without TIM in cultured cells. Light-induced TIM elimination from nuclear PER/TIMUL complexes; constitutively nuclear PER transgene behavioral analysis; cell-based transcription repression assay Neuron Medium 10839368
2002 The F-box/WD40 protein SLIMB, a component of the SCF ubiquitin ligase complex, is required for circadian degradation of phosphorylated PER and TIM proteins. In slimb mutants, highly phosphorylated forms of PER and TIM accumulate constitutively, indicating SLIMB targets phosphorylated clock proteins for degradation. Genetic analysis of slimb mutants, behavioral rhythmicity assays, Western blot of PER and TIM protein levels and phosphorylation Nature High 12432393
2003 In Drosophila ovarian follicle cells, PER and TIM are constitutively expressed, interact, but do not translocate to the nucleus. Their levels are unaffected by light or by loss of CLK/CYC, indicating a non-circadian mode of PER/TIM regulation in the ovary that is distinct from clock cells. Immunostaining in Drosophila ovaries, genetic analysis with clk, cyc, and light treatment; fertility phenotype in per and tim null mutants Journal of biological rhythms Medium 14667147
2003 Mammalian mTIM is essential for embryonic development (mouse knockout is lethal), and full-length mTIM protein oscillates with a 24-hour rhythm in the SCN and associates with mammalian PER proteins (mPERs) in SCN cells. Conditional knockdown of mTIM in rat SCN disrupts neuronal activity rhythms and alters levels of core clock elements. Conditional antisense knockdown in rat SCN, bioluminescence/electrophysiology recordings, co-immunoprecipitation from SCN extracts, Western blot of mTIM isoforms Science Medium 14564007
2003 TIPIN (Timeless-interacting protein) was identified as a novel mTIM-binding partner via yeast two-hybrid. TIPIN interacts with mTIM in vitro and in cultured cells, disrupts mTIM homo-multimer formation, and mTIM promotes nuclear localization of TIPIN. Yeast two-hybrid screen, in vitro binding, co-immunoprecipitation in transfected cells, immunofluorescence Journal of molecular biology Medium 12875843
2003 Drosophila TIM shuttles independently between nucleus and cytoplasm in vivo and in vitro. PER is not required for TIM nuclear entry but influences TIM localization; blocking nuclear export increases nuclear TIM. Nuclear TIM alone does not repress CLK/CYC-driven transcription; PER may be required for nuclear retention of TIM. Immunostaining in per mutant and wild-type larvae and S2 cells; nuclear export inhibition; transcriptional reporter assay The Journal of neuroscience Medium 12944510
2005 Human TIMELESS interacts with the circadian clock protein cryptochrome 2 (CRY2) and with cell cycle checkpoint proteins CHK1 and the ATR-ATRIP complex. Knockdown of TIMELESS in human cells severely compromises replication and intra-S checkpoints, demonstrating a role in DNA damage checkpoint responses. Co-immunoprecipitation, siRNA knockdown in human cells, DNA damage checkpoint assays (replication checkpoint, intra-S checkpoint) Molecular and cellular biology High 15798197
2006 TIPIN and TIMELESS form a mutually protective complex; loss of either protein leads to loss of the partner. TIPIN is a nuclear protein associated with the replicative helicase, required for efficient cell cycle arrest in response to DNA damage. TIPIN depletion renders cells sensitive to ionizing radiation and replication stress and causes spontaneous γ-H2AX foci. Co-immunoprecipitation, siRNA knockdown, flow cytometry, γ-H2AX immunofluorescence, clonogenic survival Proceedings of the National Academy of Sciences of the United States of America High 17116885
2006 Human TIMELESS and TIPIN are replisome-associated proteins that co-localize with BrdU-positive DNA replication sites. TIM-TIPIN directly binds the 34 kDa subunit of replication protein A (RPA34). TIM knockdown compromises DNA replication efficiency. TIPIN also associates with peroxiredoxin 2. Co-immunoprecipitation with replisome components, co-localization with BrdU replication foci, surface plasmon resonance (direct binding to RPA34), siRNA knockdown + DNA replication assay Journal of molecular biology High 17141802
2006 Human TIPIN interacts with TIM through N-terminal segments of each molecule. The TIM-TIPIN complex is present throughout the cell cycle in the nucleus with fractions in chromatin during S phase. TIPIN depletion causes radioresistant DNA synthesis, inhibits CHK1 phosphorylation under replication stress, and reduces nuclear accumulation of Claspin. TIPIN and TIM mutually stabilize each other. Co-immunoprecipitation, domain-mapping, chromatin fractionation, siRNA knockdown, CHK1 phosphorylation assay, Claspin localization The Journal of biological chemistry High 17102137
2008 CK2 kinase phosphorylates TIM in vitro and in vivo. Dominant-negative CK2α increases TIM protein levels, causes persistent cytoplasmic TIM localization, reduces oscillation amplitude, and elevates tim transcript. TIM is required for CK2 effects on PER; deletion of a conserved serine-rich domain of TIM abolishes rhythmic phosphorylation-associated mobility shifts. A putative CK2 site in TIMUL reduces period-lengthening effects of dominant-negative CK2. In vitro kinase assay (CK2 phosphorylation of TIM), dominant-negative transgene expression in Drosophila, Western blot, immunocytochemistry, genetic epistasis (tim01, per01 backgrounds) The Journal of neuroscience High 18815259
2009 Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control. TIM depletion attenuates doxorubicin-induced G2/M arrest and sensitizes cancer cells to doxorubicin-induced cytotoxicity. siRNA knockdown of TIM in human cancer cells, Western blot for CHK2 phosphorylation, flow cytometry for cell cycle, viability assays The Journal of biological chemistry Medium 19996108
2010 Human TIMELESS is recruited to replication origin regions and dissociates as replication proceeds. Timeless-Tipin depletion causes chromosome fragmentation, impairs sister chromatid cohesion, and causes mitotic defects. Timeless co-purifies with cohesin subunits and is required for their stable chromatin association during S phase. Timeless associates with the cohesion-promoting helicase ChlR1; ChlR1 overexpression partially rescues the cohesion defect. ChIP at replication origins, siRNA knockdown, chromosome fragmentation analysis, sister chromatid cohesion assays, co-immunoprecipitation with cohesin and ChlR1 Journal of cell science High 20124417
2011 Timeless is essential for EBV episomal maintenance; Tim and Tipin accumulate at the EBV OriP during S phase, and Tim depletion inhibits OriP-dependent DNA replication and causes complete loss of closed-circular EBV episomes in latently infected B cells, with accumulation of double-strand breaks at OriP. ChIP at OriP, siRNA knockdown of Tim, Southern blot for EBV episome forms, γ-H2AX analysis Journal of virology Medium 21490103
2011 In human fibroblasts, Timeless has a function in sister chromatid cohesion (SCC) independent of the Tim-Tipin complex and independent of Chk1. Timeless knockdown induces a ~100-fold increase in sister chromatid discohesion, while Tipin knockdown causes only 4–20-fold, indicating a Tipin-independent role for Timeless in SCC. siRNA knockdown of Timeless, Tipin, Claspin, Chk1, ATR; SCC assay; comparison of discohesion levels Cell cycle Medium 21508667
2012 Drosophila TIM regulates circadian resistance to bacterial infection by controlling phagocytic activity. Wild-type flies exhibit upregulated phagocytic activity at night; tim mutants lose this night-time peak. TIM appears to regulate an upstream event in phagocytosis such as bacterial recognition or activation of phagocytic hemocytes. tim mutant survival analysis, phagocytosis assays, AMP expression analysis, melanization assays in wild-type vs. tim mutant flies PLoS pathogens Medium 22253593
2012 CULLIN-3 (CUL-3) is required for circadian control of TIM oscillations. CUL-3 forms protein complexes with hypo-phosphorylated TIM (whereas SLMB preferentially targets phosphorylated TIM). CUL-3 and SLMB act additively and via different mechanisms on TIM and PER degradation. RNAi/dominant-negative of CUL-3 in Drosophila clock neurons, behavioral assays, Western blot for TIM/PER levels and phosphorylation, co-immunoprecipitation of CUL-3 with TIM PLoS biology High 22879814
2012 Timeless depletion leads to telomere shortening in human cells independently of telomerase. Timeless associates with Shelterin components TRF1 and TRF2, and TRF1 mediates accumulation of replisome components at telomeres. Timeless depletion slows telomere replication in vitro and causes telomere replication delay and DNA damage. siRNA knockdown, telomere length assays (Q-FISH, Southern blot), co-immunoprecipitation with TRF1/TRF2, in vitro telomere replication assay, immunofluorescence Cell cycle Medium 22672906
2013 Timeless is required for KSHV episome maintenance; Tim and Tipin are enriched at KSHV terminal repeats (TR) during S phase in a LANA-dependent manner. Tim depletion inhibits LANA-dependent TR DNA replication and causes loss of KSHV episomes with aberrant accumulation of recombination structures and arrested MCM helicase at TR. ChIP at KSHV TR, siRNA knockdown of Tim, 2D agarose gel analysis of replication intermediates, KSHV episome detection Journal of virology Medium 23325691
2013 Mammalian TIMELESS is involved in circadian period determination; RNAi knockdown in NIH3T3 and U2OS cells shortens the period by ~1 hour. The N-terminus of TIM is sufficient for interaction with CRY1 and CHK1, and for homodimerization; the C-terminus is necessary for nuclear localization. The long TIM isoform (l-TIM) but not the short (s-TIM) interacts with CRY1; l-TIM and CRY1 can reciprocally regulate each other's nuclear translocation. PER2 abolishes TIM/CRY1 complex formation through competition for the C-terminal tail of CRY1. RNAi in oscillating cell lines (period measurement), co-immunoprecipitation, domain-deletion mapping, nuclear translocation assay in COS7 cells PloS one Medium 23418588
2015 Human TIMELESS physically interacts with PARP-1 via a specific PARP-1-binding domain (PAB) that recognizes PARP-1 but not PARP-2 or PARP-3, independent of poly(ADP-ribosyl)ation. Crystal structures of the Timeless PAB domain alone and in complex with the PARP-1 catalytic domain were solved. Timeless recruitment to laser-induced DNA damage requires PARP-1 but not PAR. PARP-1-TIMELESS interaction is required for efficient homologous recombination repair. Co-immunoprecipitation, crystal structure (X-ray crystallography), laser-microirradiation + live imaging, HR repair assay, PARP-1 enzymatic activity assay Molecular cell High 26344098
2015 TIMELESS forms a complex with PARP-1 that is distinct from the TIMELESS-TIPIN complex. TIMELESS recruitment to DNA damage sites is PARP-1-dependent but PAR-independent. TIMELESS knockdown impairs PARP-1 binding to certain substrates, their recruitment to DNA damage lesions, and DNA double-strand break repair. Co-immunoprecipitation, laser-induced DNA damage + immunofluorescence, siRNA knockdown, DSB repair assay Cell reports Medium 26456830
2015 Tim physically and functionally interacts with DDX11 helicase; Tim stimulates DDX11 unwinding activity on forked DNA substrates up to 10-fold, on G-quadruplex DNA ~4–5-fold, and on D-loop ~4–5-fold. Tim enhances DDX11 binding to DNA substrates. Tim and DDX11 are epistatic for replication fork progression and recovery from stalled forks in HeLa cells. In vitro helicase assay, electrophoretic mobility shift assay, surface plasmon resonance (direct binding), DNA fiber track assay, siRNA co-depletion epistasis Nucleic acids research High 26503245
2016 GSK-3/SGG binds and phosphorylates PER-bound TIM in Drosophila master pacemaker neurons, triggering a subsequent CK2-mediated phosphorylation cascade that controls the timing of nuclear accumulation of the PER/TIM repressor complex. Mutations blocking this hierarchical phosphorylation delay nuclear accumulation and alter circadian behavior. This two-kinase cascade is restricted to the eight master pacemaker neurons. In vitro kinase assay (GSK-3 phosphorylation of TIM), genetic mutations blocking phosphorylation sites, tissue culture nuclear accumulation assay, immunocytochemistry in vivo, behavioral period analysis Cell reports High 27346344
2018 Ubiquitylation of TIM in Drosophila is mediated cooperatively by both CULLIN-3 and SLMB ubiquitin ligase subunits, which collaborate to ubiquitylate TIMELESS protein during the circadian cycle. In vivo ubiquitin labeling assay, co-immunoprecipitation, mass spectrometry, genetic analysis Cell reports Medium 29791839
2018 PRP4 kinase (a U4/U5.U6 tri-snRNP spliceosome component) and other tri-snRNP components regulate the Drosophila circadian clock by controlling alternative splicing of timeless (tim) pre-mRNA. Increased intron retention in tim upon prp4 downregulation decreases TIM levels. Tim splicing is rhythmic with a phase that parallels delayed TIM protein accumulation. RNAi screen, RNA-seq, RT-PCR splicing analysis, behavioral rhythmicity assay, protein level analysis eLife Medium 30516472
2019 Claspin and Timeless overexpression protects cancer cells from replication stress (RS) by protecting replication forks in a checkpoint-independent manner. Reducing Claspin and Timeless to pre-tumoral levels impedes fork progression without affecting checkpoint signaling. Primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless independently of ATR signaling. siRNA knockdown to pre-tumoral levels, DNA fiber assay (fork progression), checkpoint signaling Western blot, oncogene-induced RS model in fibroblasts Nature communications Medium 30796221
2019 A human TIMELESS mutation causes familial advanced sleep phase (FASP). The mutation prevents TIM nuclear accumulation and reduces TIM affinity for CRY2, leading to destabilization of the PER/CRY complex and shorter circadian period in mouse embryonic fibroblasts. CRISPR mutant mice exhibit FASP with altered photic entrainment. Human genetics (FASP family), CRISPR mutant mice (behavioral analysis), nuclear localization assay, co-immunoprecipitation (TIM-CRY2 interaction), period measurement in MEFs Proceedings of the National Academy of Sciences of the United States of America High 31138685
2020 TIMELESS harbors a C-terminal DNA-binding domain with specific affinity for G-quadruplex (G4) DNA structures. This domain contributes to maintaining processive replication through G4-forming sequences and exhibits partial redundancy with the adjacent PARP-binding domain. TIMELESS function at G4 structures requires interaction with and helicase activity of DDX11; loss of both causes epigenetic instability and DNA damage at G4-forming sequences. Biochemical DNA-binding assay (EMSA with G4 DNA), domain deletion/mutagenesis, DNA fiber assay, epistasis analysis with DDX11, epigenetic instability assay The EMBO journal High 32705708
2020 SDE2 directly interacts with TIMELESS and enhances its stability, aiding TIM localization to replication forks. SDE2 depletion, like TIM depletion, impairs fork progression, stalled fork recovery, and CHK1 phosphorylation activation. Both TIM and SDE2 protect stalled forks from excessive MRE11-dependent degradation of reversed forks. Co-immunoprecipitation, siRNA knockdown, DNA fiber assay, CHK1 phosphorylation assay, reversed fork degradation assay (PLA/fiber) Nature communications Medium 33127907
2020 In Drosophila, EYES ABSENT (EYA) acts as a seasonal sensor aided by the stabilizing action of TIMELESS. Increased TIM stability at night under short photoperiod and production of cold-induced, light-insensitive TIM isoforms facilitate EYA accumulation in winter conditions. tim null mutants exhibit reduced reproductive dormancy in simulated winter conditions. Tissue-specific genetic manipulation of eya and tim, reproductive dormancy phenotype assays, protein stability analysis Proceedings of the National Academy of Sciences of the United States of America Medium 32541062
2021 The TIMELESS-TIPIN complex is required for CUL-2LRR-1 recruitment and efficient CMG helicase ubiquitylation during DNA replication termination in C. elegans. Aided by TIMELESS-TIPIN, CUL-2LRR-1 directs ubiquitylation enzymes to ubiquitylate MCM-7 subunit of CMG, facilitating replisome disassembly by CDC-48. Co-depletion of UBXN-3 (human FAF1 ortholog) and TIMELESS causes profound synthetic lethality. In vitro reconstitution of CMG ubiquitylation, in vivo C. elegans genetics, epistasis analysis, co-depletion lethality assay The EMBO journal High 34269473
2023 Cryo-EM structure of the Drosophila CRY-TIM complex reveals that CRY engages a continuous core of N-terminal TIM armadillo repeats (resembling photolyase-DNA recognition) and binds a C-terminal TIM helix. The Cry flavin cofactor undergoes conformational changes coupled to large-scale rearrangements at the CRY-TIM interface. A phosphorylated segment of TIM may regulate Importin-α binding and TIM-PER nuclear import. The N-terminus of TIM inserts into the restructured CRY pocket to replace the autoinhibitory CRY C-terminal tail released by light, explaining how the long-short TIM polymorphism affects light sensitivity. Cryo-electron microscopy (cryo-EM) structure determination, structural analysis of CRY-TIM interface Nature High 37100907

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 581 9630223
1998 CYCLE is a second bHLH-PAS clock protein essential for circadian rhythmicity and transcription of Drosophila period and timeless. Cell 513 9630224
1994 Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science (New York, N.Y.) 472 8128246
1999 Light-dependent sequestration of TIMELESS by CRYPTOCHROME. Science (New York, N.Y.) 445 10417378
1996 Light-induced degradation of TIMELESS and entrainment of the Drosophila circadian clock. Science (New York, N.Y.) 373 8596937
2000 Neuroanatomy of cells expressing clock genes in Drosophila: transgenic manipulation of the period and timeless genes to mark the perikarya of circadian pacemaker neurons and their projections. The Journal of comparative neurology 333 10842219
1996 Regulation of the Drosophila protein timeless suggests a mechanism for resetting the circadian clock by light. Cell 325 8625406
1998 Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron 303 9856465
1995 Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science (New York, N.Y.) 293 7481772
1995 Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science (New York, N.Y.) 291 7481773
1994 Block in nuclear localization of period protein by a second clock mutation, timeless. Science (New York, N.Y.) 281 8128247
1996 Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron 274 8938123
2005 Coupling of human circadian and cell cycles by the timeless protein. Molecular and cellular biology 252 15798197
2002 The F-box protein slimb controls the levels of clock proteins period and timeless. Nature 226 12432393
1997 Spatial and temporal expression of the period and timeless genes in the developing nervous system of Drosophila: newly identified pacemaker candidates and novel features of clock gene product cycling. The Journal of neuroscience : the official journal of the Society for Neuroscience 210 9254686
1995 Positional cloning and sequence analysis of the Drosophila clock gene, timeless. Science (New York, N.Y.) 192 7481771
1995 Suppression of PERIOD protein abundance and circadian cycling by the Drosophila clock mutation timeless. The EMBO journal 180 7664743
2003 Requirement of mammalian Timeless for circadian rhythmicity. Science (New York, N.Y.) 158 14564007
1998 Molecular analysis of mammalian timeless. Neuron 147 9856466
2006 Tipin and Timeless form a mutually protective complex required for genotoxic stress resistance and checkpoint function. Proceedings of the National Academy of Sciences of the United States of America 142 17116885
2000 A time-less function for mouse timeless. Nature neuroscience 138 10903565
2000 A TIMELESS-independent function for PERIOD proteins in the Drosophila clock. Neuron 128 10839368
2006 Human Tim/Timeless-interacting protein, Tipin, is required for efficient progression of S phase and DNA replication checkpoint. The Journal of biological chemistry 114 17102137
2006 Mammalian TIMELESS and Tipin are evolutionarily conserved replication fork-associated factors. Journal of molecular biology 114 17141802
2010 Human Timeless and Tipin stabilize replication forks and facilitate sister-chromatid cohesion. Journal of cell science 113 20124417
2019 Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner. Nature communications 110 30796221
1998 Response of the timeless protein to light correlates with behavioral entrainment and suggests a nonvisual pathway for circadian photoreception. Neuron 107 9697865
2015 Timeless Interacts with PARP-1 to Promote Homologous Recombination Repair. Molecular cell 106 26344098
2014 Dual PDF signaling pathways reset clocks via TIMELESS and acutely excite target neurons to control circadian behavior. PLoS biology 100 24643294
1996 Three hTIM mutants that provide new insights on why TIM is a dimer. Journal of molecular biology 95 8609635
2019 Ricin: An Ancient Story for a Timeless Plant Toxin. Toxins 89 31174319
2012 The circadian clock protein timeless regulates phagocytosis of bacteria in Drosophila. PLoS pathogens 83 22253593
2003 Noncircadian regulation and function of clock genes period and timeless in oogenesis of Drosophila melanogaster. Journal of biological rhythms 82 14667147
2012 Local and global functions of Timeless and Tipin in replication fork protection. Cell cycle (Georgetown, Tex.) 79 22987152
2009 Mammalian TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control. The Journal of biological chemistry 78 19996108
2006 Veela defines a molecular link between Cryptochrome and Timeless in the light-input pathway to Drosophila's circadian clock. Proceedings of the National Academy of Sciences of the United States of America 78 17068124
1996 The timSL mutant of the Drosophila rhythm gene timeless manifests allele-specific interactions with period gene mutants. Neuron 78 8938124
2002 Short-day and long-day expression patterns of genes involved in the flesh fly clock mechanism: period, timeless, cycle and cryptochrome. Journal of insect physiology 76 12770058
2015 TIMELESS Forms a Complex with PARP1 Distinct from Its Complex with TIPIN and Plays a Role in the DNA Damage Response. Cell reports 67 26456830
2012 Timeless preserves telomere length by promoting efficient DNA replication through human telomeres. Cell cycle (Georgetown, Tex.) 65 22672906
2020 Timeless couples G-quadruplex detection with processing by DDX11 helicase during DNA replication. The EMBO journal 64 32705708
1998 Conserved regions of the timeless (tim) clock gene in Drosophila analyzed through phylogenetic and functional studies. Genetics 64 9504927
2000 Isolation and analysis of six timeless alleles that cause short- or long-period circadian rhythms in Drosophila. Genetics 63 11014814
2013 Mammalian TIMELESS is involved in period determination and DNA damage-dependent phase advancing of the circadian clock. PloS one 62 23418588
1998 Identification of the mammalian homologues of the Drosophila timeless gene, Timeless1. FEBS letters 62 9891984
2019 Timeless-Stimulated miR-5188-FOXO1/β-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of β-Catenin in Breast Cancer. Molecular therapy : the journal of the American Society of Gene Therapy 61 31604679
2011 Genetic and epigenetic associations of circadian gene TIMELESS and breast cancer risk. Molecular carcinogenesis 58 22006848
2021 Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. Journal of neural transmission (Vienna, Austria : 1996) 57 33624170
2015 Tim/Timeless, a member of the replication fork protection complex, operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same fork recovery pathway. Nucleic acids research 57 26503245
2020 EYES ABSENT and TIMELESS integrate photoperiodic and temperature cues to regulate seasonal physiology in Drosophila. Proceedings of the National Academy of Sciences of the United States of America 56 32541062
2003 Novel insights into the regulation of the timeless protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 56 12944510
2003 Tipin, a novel timeless-interacting protein, is developmentally co-expressed with timeless and disrupts its self-association. Journal of molecular biology 55 12875843
2013 TIMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival. Cancer science 54 23173913
2006 Structure and expressions of two circadian clock genes, period and timeless in the commercial silkmoth, Bombyx mori. Journal of insect physiology 53 16626732
2017 TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/β-catenin signaling pathway and promoting the epithelial mesenchymal transition. Cancer letters 52 28583847
2016 GSK-3 and CK2 Kinases Converge on Timeless to Regulate the Master Clock. Cell reports 52 27346344
2019 TIMELESS mutation alters phase responsiveness and causes advanced sleep phase. Proceedings of the National Academy of Sciences of the United States of America 50 31138685
1999 TIMELESS-dependent positive and negative autoregulation in the Drosophila circadian clock. The EMBO journal 49 9927427
2023 Cryptochrome-Timeless structure reveals circadian clock timing mechanisms. Nature 47 37100907
2022 Loss of Timeless Underlies an Evolutionary Transition within the Circadian Clock. Molecular biology and evolution 47 34893879
2015 A Timeless Link Between Circadian Patterns and Disease. Trends in molecular medicine 46 26691298
2012 CULLIN-3 controls TIMELESS oscillations in the Drosophila circadian clock. PLoS biology 45 22879814
2023 Exosomal-miR-129-2-3p derived from Fusobacterium nucleatum-infected intestinal epithelial cells promotes experimental colitis through regulating TIMELESS-mediated cellular senescence pathway. Gut microbes 44 37550944
2016 mir-276a strengthens Drosophila circadian rhythms by regulating timeless expression. Proceedings of the National Academy of Sciences of the United States of America 43 27162360
1996 Protein folding for realists: a timeless phenomenon. Protein science : a publication of the Protein Society 42 8762131
2005 Geographic and developmental variation in expression of the circadian rhythm gene, timeless, in the pitcher-plant mosquito, Wyeomyia smithii. Journal of insect physiology 41 15979087
2006 A Timeless debate: resolving TIM's noncircadian roles with possible clock function. Neuroreport 40 16951560
2020 TIMELESS regulates sphingolipid metabolism and tumor cell growth through Sp1/ACER2/S1P axis in ER-positive breast cancer. Cell death & disease 39 33093451
2020 SDE2 integrates into the TIMELESS-TIPIN complex to protect stalled replication forks. Nature communications 39 33127907
2002 Mapping of elements involved in regulating normal temporal period and timeless RNA expression patterns in Drosophila melanogaster. Journal of biological rhythms 39 12164246
2017 TIMELESS contributes to the progression of breast cancer through activation of MYC. Breast cancer research : BCR 37 28464854
2008 Timeless Maintains Genomic Stability and Suppresses Sister Chromatid Exchange during Unperturbed DNA Replication. The Journal of biological chemistry 36 19112184
2000 A role for Timeless in epithelial morphogenesis during kidney development. Proceedings of the National Academy of Sciences of the United States of America 36 10963667
1999 Oscillation and light induction of timeless mRNA in the mammalian circadian clock. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 10366653
2006 A nondiapausing variant of the flesh fly, Sarcophaga bullata, that shows arrhythmic adult eclosion and elevated expression of two circadian clock genes, period and timeless. Journal of insect physiology 35 17054977
2010 RNA interference of timeless gene does not disrupt circadian locomotor rhythms in the cricket Gryllus bimaculatus. Journal of insect physiology 34 20637213
2022 Loss of circadian gene Timeless induces EMT and tumor progression in colorectal cancer via Zeb1-dependent mechanism. Cell death and differentiation 33 35034102
2019 ERK-mediated TIMELESS expression suppresses G2/M arrest in colon cancer cells. PloS one 33 30629587
2014 Protumorigenic role of Timeless in hepatocellular carcinoma. International journal of oncology 33 25405317
2013 Potential cancer-related role of circadian gene TIMELESS suggested by expression profiling and in vitro analyses. BMC cancer 33 24161199
2015 period and timeless mRNA Splicing Profiles under Natural Conditions in Drosophila melanogaster. Journal of biological rhythms 32 25994101
2008 TIMELESS is an important mediator of CK2 effects on circadian clock function in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 32 18815259
2006 Cloning and daily expression of the timeless gene in Aedes aegypti (Diptera:Culicidae). Insect biochemistry and molecular biology 31 17046601
2001 Regulation of the cycling of timeless (tim) RNA. Journal of neurobiology 31 11333398
2018 Ubiquitylation Dynamics of the Clock Cell Proteome and TIMELESS during a Circadian Cycle. Cell reports 30 29791839
2011 Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts. Cell cycle (Georgetown, Tex.) 30 21508667
2023 Evolving Horizons: Adenovirus Vectors' Timeless Influence on Cancer, Gene Therapy and Vaccines. Viruses 29 38140619
2021 Activation of the clock gene TIMELESS by H3k27 acetylation promotes colorectal cancer tumorigenesis by binding to Myosin-9. Journal of experimental & clinical cancer research : CR 29 33971927
2018 Spliceosome factors target timeless (tim) mRNA to control clock protein accumulation and circadian behavior in Drosophila. eLife 28 30516472
2022 Identification of TIMELESS and RORA as key clock molecules of non-small cell lung cancer and the comprehensive analysis. BMC cancer 26 35078435
2003 Timeless in lung morphogenesis. Developmental dynamics : an official publication of the American Association of Anatomists 26 12950082
2023 The TIMELESS effort for timely DNA replication and protection. Cellular and molecular life sciences : CMLS 25 36892674
2021 Timeless in animal circadian clocks and beyond. The FEBS journal 25 34699674
2020 Aberrantly Expressed Timeless Regulates Cell Proliferation and Cisplatin Efficacy in Cervical Cancer. Human gene therapy 25 31870179
2020 CRISPR/Cas9-based knockout reveals that the clock gene timeless is indispensable for regulating circadian behavioral rhythms in Bombyx mori. Insect science 25 32830431
2016 Aberrant TIMELESS expression is associated with poor clinical survival and lymph node metastasis in early-stage cervical carcinoma. International journal of oncology 25 27909716
2013 Timeless-dependent DNA replication-coupled recombination promotes Kaposi's Sarcoma-associated herpesvirus episome maintenance and terminal repeat stability. Journal of virology 25 23325691
2011 The replisome pausing factor Timeless is required for episomal maintenance of latent Epstein-Barr virus. Journal of virology 25 21490103
2022 MEX3A promotes the malignant progression of ovarian cancer by regulating intron retention in TIMELESS. Cell death & disease 24 35715407
2021 TIMELESS-TIPIN and UBXN-3 promote replisome disassembly during DNA replication termination in Caenorhabditis elegans. The EMBO journal 24 34269473

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