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FLASH GENE

Symbol

TIMELESS

contributors: mct/npt/pgu - updated : 21-05-2016

HGNC name	timeless homolog (Drosophila)
HGNC id	11813

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Location	12q13.2      Physical location : 56.810.156 - 56.843.200
Synonym name	timeless homolog
Synonym symbol(s)	TIM, HTIM, TIM1, FLJ12640, FLJ20714, TIMELESS1

DNA

TYPE	functioning gene
STRUCTURE	33.04 kb     29 Exon(s)

10 Kb 5' upstream gene genomic sequence study

MAPPING

cloned

Y

linked

N

status

provisional

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_003920 29 - 5154 NP_003911 - 1208 - 1998 9891984

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Endocrine pancreas       highly Lymphoid/Immune thymus       highly Nervous brain forebrain cerebral cortex     Homo sapiens   brain limbic system       Homo sapiens Reproductive male system testis     highly   male system prostate     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone     moderately Epithelial secretory glandular endocrine   Epithelial secretory glandular exocrine   Lymphoid

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Homo sapiens

cell lineage
cell lines
fluid/secretion	highly in lymph

at STAGE

physiological period

pregnancy

Text	highly in placenta

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	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

HOMOLOGY

interspecies	homolog to rattus Timeless (83.1 pc)
	homolog to murine Timeless (84.7 pc)

Homologene

FAMILY

Timeless family

CATEGORY

regulatory

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,chromatin/chromosome
	intracellular,nucleus,nucleolus
text	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

text	branching morphogenesis of a tube
	lung development
	morphogenesis of an epithelium

PATHWAY

metabolism

signaling

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

INTERACTION

DNA

RNA

small molecule

protein	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

REGULATION

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)

ASSOCIATED DISORDERS

corresponding disease(s)

Susceptibility

Variant & Polymorphism

Candidate gene
Marker	potential biomarker of cancer susceptibility and prognostic outcome
Therapy target

ANIMAL & CELL MODELS