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Symbol TIMELESS contributors: mct/npt/pgu - updated : 21-05-2016
HGNC name timeless homolog (Drosophila)
HGNC id 11813
  • N-terminus is sufficient for interaction with CRY1 and CHEK1 as well for homodimerization
  • protein-protein interaction with PER and cytoplasmic localization
  • C-terminus necessary for nuclear localization
  • conjugated PhosphoP
    mono polymer homomer , heteromer , dimer , complex
    interspecies homolog to rattus Timeless (83.1 pc)
    homolog to murine Timeless (84.7 pc)
  • Timeless family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
  • is expressed in neuronal tissues in a spatiotemporally regulated manner and involved in developmental stage-specific neuronal functions
  • basic FUNCTION
  • involved in circadian oscillation autoregulation and in regulation of meiotic chromosome cohesion
  • inhibiting CLOCK-BMAL1-induced transactivation
  • may play an important role in epithelial cell morphogenesis and formation of branching tubules
  • required for CK2 effects on PER, and is an important mediator of CK2 effects on circadian rhythms
  • TIMELESS-TIPIN complex stabilizes replication forks both by preventing the accumulation of ssDNA upstream of ATR-CHEK1 function and by facilitating phosphorylation of CHEK1 by ATR
  • required for ATM-dependent activation of CHEK2 and G2/M checkpoint arrest
  • TIMELESS has a function in sister chromatid cohesion (SCC) that is independent of the TIMELESS-TIPIN complex, even though the abundance of TIMELESS is reduced when TIPIN is targeted for depletion
  • coordinates mitotic kinase activation with termination of DNA replication
  • functions together with TERF1 to prevent fork collapse at telomere repeat DNA and ensure stable maintenance of telomere length and integrity
  • implicated in circadian rhythms as well as cell cycle control and embryonic development
  • TIMELESS is responsible for the interaction between the TIMELESS-TIPIN and Mcm complexes
  • TIMELESS-TIPIN complex plays important roles in S phase progression, stabilization of stalled replication forks, and checkpoint activation
  • TIMELESS-mediated fork protection may represent a way to cooperate with BRCA-dependent fork stabilization
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS circadian , development
  • branching morphogenesis of a tube
  • lung development
  • morphogenesis of an epithelium
    a component
  • component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, BMAL1 or BMAL2, CSKN1D and/or CSNK1E, and the PER proteins
  • WDHD1-CLSPN-TIPIN-TIMELESS complex, which coordinate DNA unwinding with polymerase alpha-, delta-, and epsilon- dependent DNA polymerization are constituents of the Replisome
  • TIMELESS-TIPIN complex, a component of the replication fork machinery, plays a role in replication checkpoint activation and stabilization of the replication fork
    small molecule
  • interacting directly with PER1 and PER2 and PER3
  • binding CRY1, CRY2, CHK1, ATR and ATRIP
  • TIMELESS protein associates with S phase replication checkpoint proteins CLSPN and TIPIN , and plays an important role in maintaining replication fork stability at physical barriers, like centromeres, telomeres and ribosomal DNA repeats, as well as at termination sites
  • is associated with Shelterin components TERF1 and TERF2
  • SH3 domain-binding protein and substrate for several members of the SRC protein-tyrosine kinase family, including FYN, SRC
  • TIMELESS-TIPIN complex might couple DNA unwinding and DNA synthesis by affecting the biochemical properties of these replisome proteins
  • SDE2 directly interacts with the FPC component TIMELESS (TIM) and enhances its stability, thereby aiding TIM localization to replication forks and the coordination of replisome progression
  • cell & other
    inhibited by by siRNA (inhibition enhancing the cytotoxic effectiveness of chemotherapeutic drugs known to activate DNA response pathways within cancer cells)
    Other regulated by the cell cycle (high levels in S, G(2) and M phases, with highest level in S phase and low expression in G(0) and G(1) phases)
    regulated by CK2 (role for CK2 in TIMELESS regulation)
    corresponding disease(s)
    Variant & Polymorphism
    Candidate gene
  • potential biomarker of cancer susceptibility and prognostic outcome
  • Therapy target