TIMELESS

Summary

TIMELESS (timeless circadian regulator, HGNC:11813) is a protein-coding gene on chromosome 12q13.3, encoding Protein timeless homolog (Q9UNS1). 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. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines).

The protein encoded by this gene is highly conserved and is involved in cell survival after damage or stress, increase in DNA polymerase epsilon activity, maintenance of telomere length, and epithelial cell morphogenesis. The encoded protein also plays a role in the circadian rhythm autoregulatory loop, interacting with the PERIOD genes (PER1, PER2, and PER3) and others to downregulate activation of PER1 by CLOCK/ARNTL. Changes in this gene or its expression may promote prostate cancer, lung cancer, breast cancer, and mental disorders.

Source: NCBI Gene 8914 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 215 total — 1 pathogenic
• Phenotypes (HPO): 2
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_003920

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11813
Approved symbol	TIMELESS
Name	timeless circadian regulator
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	hTIM, TIM, TIM1
Ensembl gene	ENSG00000111602
Ensembl biotype	protein_coding
OMIM	603887
Entrez	8914

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 retained_intron

ENST00000229201, ENST00000553314, ENST00000553532, ENST00000555808, ENST00000557589, ENST00000865170, ENST00000865171, ENST00000865172, ENST00000865173, ENST00000927920, ENST00000927921, ENST00000927922, ENST00000927923, ENST00000927924, ENST00000927925, ENST00000927926, ENST00000971076

RefSeq mRNA: 2 — MANE Select: NM_003920 NM_001330295, NM_003920

CCDS: CCDS81699, CCDS8918

Canonical transcript exons

ENST00000553532 — 29 exons

Exon	Start	End
ENSE00000749520	56433773	56433926
ENSE00001116673	56431471	56431604
ENSE00001145588	56420963	56421134
ENSE00001145598	56421351	56421493
ENSE00001145604	56421727	56421809
ENSE00001145647	56423584	56423707
ENSE00001145662	56424762	56424913
ENSE00001181800	56428236	56428405
ENSE00001181811	56428883	56429100
ENSE00001181818	56430105	56430281
ENSE00001282517	56425015	56425152
ENSE00001282528	56428549	56428652
ENSE00001282545	56430881	56430968
ENSE00001282558	56432369	56432524
ENSE00001282564	56433026	56433127
ENSE00001282571	56433381	56433443
ENSE00001282578	56433538	56433652
ENSE00001391242	56434074	56434231
ENSE00002437580	56416363	56417786
ENSE00002438456	56449310	56449426
ENSE00003460637	56420569	56420687
ENSE00003462679	56423797	56423894
ENSE00003516106	56422847	56422992
ENSE00003524256	56418134	56418359
ENSE00003534010	56422106	56422191
ENSE00003564656	56417907	56418008
ENSE00003572682	56420813	56420881
ENSE00003599354	56423274	56423475
ENSE00003672242	56421899	56422016

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 93.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.4714 / max 108.6483, expressed in 1709 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131523	15.7973	1707
131524	0.3652	211
131525	0.3089	150

Top tissues by expression

281 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	93.06	gold quality
embryo	UBERON:0000922	91.84	gold quality
ganglionic eminence	UBERON:0004023	91.51	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.95	gold quality
mucosa of transverse colon	UBERON:0004991	84.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.38	gold quality
right lobe of liver	UBERON:0001114	83.84	gold quality
vermiform appendix	UBERON:0001154	82.09	gold quality
stromal cell of endometrium	CL:0002255	82.07	gold quality
islet of Langerhans	UBERON:0000006	81.83	gold quality
endometrium epithelium	UBERON:0004811	81.66	gold quality
lymph node	UBERON:0000029	81.64	gold quality
rectum	UBERON:0001052	81.53	gold quality
granulocyte	CL:0000094	81.34	gold quality
bone marrow	UBERON:0002371	80.99	gold quality
esophagus mucosa	UBERON:0002469	80.84	gold quality
spleen	UBERON:0002106	80.45	gold quality
adenohypophysis	UBERON:0002196	79.79	gold quality
bone element	UBERON:0001474	79.17	gold quality
lower esophagus mucosa	UBERON:0035834	78.96	gold quality
bone marrow cell	CL:0002092	78.93	gold quality
caecum	UBERON:0001153	78.74	gold quality
pituitary gland	UBERON:0000007	78.71	gold quality
metanephros cortex	UBERON:0010533	78.71	gold quality
right adrenal gland cortex	UBERON:0035827	78.62	gold quality
right adrenal gland	UBERON:0001233	78.46	gold quality
body of pancreas	UBERON:0001150	78.44	gold quality
pancreas	UBERON:0001264	78.44	gold quality
amniotic fluid	UBERON:0000173	77.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	77.61	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR3C1, TP53

miRNA regulators (miRDB)

52 targeting TIMELESS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-2681-5P	99.75	67.64	1655
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-6828-5P	99.31	69.21	1433

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• 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)
• TIMELESS is required for ATM-dependent CHK2 activation and G2/M checkpoint control (PMID:19996108)
• 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)
• 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 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)
• These findings demonstrate that Tim is essential for sustaining the episomal forms of EBV DNA in latently infected cells. (PMID:21490103)
• 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)
• 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)
• All lung cancer specimens but no matched normal lung tissues were positive for TIM expression. (PMID:23173913)
• TIMELESS has a distinct contribution to suppression of chromosomal instability that is independent of its heterodimeric partner, TIPIN. (PMID:23255133)
• Kaposi’s Sarcoma-associated herpesvirus episome maintenance requires Tim-assisted replication fork protection at the viral terminal repeats. (PMID:23325691)
• 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)
• Tim-Tipin complex (or Tim alone) is able to associate with DNA polymerase epsilon bound to a 40-/80-mer DNA ligand. (PMID:23511638)
• 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)
• The results of this study suggest that the TIMELESS gene may be associated with the lithium prophylactic response in bipolar illness. (PMID:24636202)
• TIMELESS and RORA genes may confer susceptibility to bipolar disorders and impact on circadian phenotypes (PMID:24716566)
• overexpression of TIM exerts oncogenic function in human HCCs, which is mediated via CHEK2 and EEF1A2. (PMID:25405317)
• 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)
• TIMELESS mutants unable to bind PARP1. TIMELESS silencing significantly impairs DNA double-strand break repair. (PMID:26456830)
• 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)
• 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)
• 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)
• TIM rs2291738 was associated with chronotype dimensions (PMID:28708003)
• Results provide evidence that Timeless displays the characteristics of an ERalpha co-activator: it binds directly to ERalpha, increases its transcriptional activity, and is required for full ERalpha activity. This activity likely contributes to the ability of Timeless to promote breast cancer cell proliferation and may underlie the observed associations between Timeless and breast cancer patient outcome. (PMID:29555554)
• TIMELESS participates in the regulation of cellular senescence. (PMID:30100061)
• The C allele at the rs631090 locus of C1q, the G allele at 1525A/G site of TRAIL, and the G allele of Tim-1 at -1454G/A site are susceptibility variants associated with SLE. The frequency of the G allele at -1454G/A of Tim-1 was dramatically higher in the study group than in the control group. (PMID:30183357)
• 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)
• Results indicate a role for the DDX11-Timeless interaction in coordinating DNA replication with sister chromatid cohesion, and suggest implications for understanding the molecular basis of Warsaw breakage syndrome (WABS). (PMID:30303954)
• ERK activation promotes TIMELESS expression in colon cancer cell lines. TIMELESS depletion increases gammaH2AX, a marker of DNA damage, and triggers G2/M arrest via increased CHK1 and CDK1 phosphorylation. (PMID:30629587)
• the data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from oncogene-induced replication stress in a checkpoint-independent manner. (PMID:30796221)
• The mutation prevents TIM accumulation in the nucleus and has altered affinity for CRY2. (PMID:31138685)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	timeless	ENSDARG00000078497
mus_musculus	Timeless	ENSMUSG00000039994
rattus_norvegicus	Timeless	ENSRNOG00000031916
drosophila_melanogaster	timeout	FBGN0038118
caenorhabditis_elegans		WBGENE00006571

Protein

Protein identifiers

Protein timeless homolog — Q9UNS1 (reviewed: Q9UNS1)

All UniProt accessions (1): Q9UNS1

UniProt curated annotations — full annotation on UniProt →

Function. 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. During DNA replication, inhibits the CMG complex ATPase activity and activates DNA polymerases catalytic activities, coupling DNA unwinding and DNA synthesis. TIMELESS promotes TIPIN nuclear localization. Plays a role in maintaining processive DNA replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures, possibly together with DDX11. 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 play a role as destabilizer of the PER2-CRY2 complex. May also play an important role in epithelial cell morphogenesis and formation of branching tubules.

Subunit / interactions. Monomer. Homodimer or homomultimer. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK or NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and the PER proteins. Interacts with PER2. The interaction with PER2 is direct and via its second PAS domain. Interacts directly with PER1 and PER3. Interacts with CRY2, CHEK1, ATR and ATRIP. Interacts with CRY1. Interacts with CLSPN; the interaction is required for leading-strand replication. Interacts (via N-terminus) with TIPIN. The TIMELESS-TIPIN heterodimer binds preferably to guanine-rich quadruplex-forming (G4) DNA structures. Associates with the MCM2-7 complex. Interacts with DNA polymerases alpha, delta and epsilon. Interacts with DDX11; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea. Interacts with PARP1; interaction is direct and independent of poly-ADP-ribose.

Subcellular location. Nucleus. Chromosome.

Tissue specificity. 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.

Disease relevance. Advanced sleep phase syndrome, familial, 4 (FASPS4) [MIM:620015] An autosomal dominant disorder characterized by very early sleep onset and offset. Individuals are ‘morning larks’ with a 4 hours advance of the sleep, temperature and melatonin rhythms. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Residues 1182-1199 comprise a putative nuclear localization signal; nuclear localization is required for the regulation of period length of the circadian clock. The DNA-binding domain (residues 816-954) binds to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), and has high affinity for DNA sequences rich in guanine that form G-quadruplex (G4) structures. The C-terminal domain, comprising the DNA-binding domain and the PARP1-binding region, is required for the replication past genomic guanine-rich DNA sequences that form G-quadruplex (G4) structures.

Induction. Regulated by the cell cycle. High levels in S, G(2) and M phases, with highest level in S phase. Low expression in G(0) and G(1) phases.

Similarity. Belongs to the timeless family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UNS1-1	1	yes
Q9UNS1-2	2

RefSeq proteins (2): NP_001317224, NP_003911* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006906	Timeless_N	Domain
IPR007725	TIMELESS_PAB	Domain
IPR044998	Timeless	Family

Pfam: PF04821, PF05029, PF26019

UniProt features (78 total): helix 37, sequence variant 12, region of interest 8, modified residue 6, strand 6, compositionally biased region 4, turn 2, chain 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6T9Q	X-RAY DIFFRACTION	1.15
4XHT	X-RAY DIFFRACTION	1.65
5MQI	X-RAY DIFFRACTION	1.85
4XHU	X-RAY DIFFRACTION	2.09
7PLO	ELECTRON MICROSCOPY	2.8
4XHW	X-RAY DIFFRACTION	2.85
7PFO	ELECTRON MICROSCOPY	3.2
8B9D	ELECTRON MICROSCOPY	3.4
6TAZ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UNS1-F1	74.56	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (6): 281, 1074, 1087, 1089, 1149, 1173

Mutagenesis-validated functional residues (1):

Position	Phenotype
1081	abolishes interaction with parp1.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5693607	Processing of DNA double-strand break ends

MSigDB gene sets: 340 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CIRCADIAN_RHYTHM, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, MODULE_255, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MODULE_317, FRASOR_RESPONSE_TO_SERM_OR_FULVESTRANT_DN, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION

GO Biological Process (20): DNA replication checkpoint signaling (GO:0000076), morphogenesis of an epithelium (GO:0002009), DNA repair (GO:0006281), DNA damage response (GO:0006974), circadian rhythm (GO:0007623), detection of abiotic stimulus (GO:0009582), lung development (GO:0030324), replication fork processing (GO:0031297), regulation of circadian rhythm (GO:0042752), replication fork arrest (GO:0043111), cell cycle phase transition (GO:0044770), negative regulation of DNA-templated transcription (GO:0045892), branching morphogenesis of an epithelial tube (GO:0048754), cell division (GO:0051301), cellular response to hydroxyurea (GO:0072711), cellular response to cisplatin (GO:0072719), cellular response to bleomycin (GO:1904976), positive regulation of double-strand break repair via homologous recombination (GO:1905168), positive regulation of double-strand break repair (GO:2000781), rhythmic process (GO:0048511)

GO Molecular Function (4): DNA binding (GO:0003677), enzyme activator activity (GO:0008047), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), replication fork protection complex (GO:0031298), site of double-strand break (GO:0035861), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated DNA replication maintenance of fidelity	2
cellular response to nitrogen compound	2
cellular anatomical structure	2
DNA integrity checkpoint signaling	1
tissue morphogenesis	1
epithelium development	1
DNA metabolic process	1
DNA damage response	1
cellular response to stress	1
rhythmic process	1
response to abiotic stimulus	1
detection of stimulus	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
circadian rhythm	1
regulation of biological process	1
negative regulation of DNA-templated DNA replication	1
cell cycle process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
tube morphogenesis	1
epithelial tube morphogenesis	1
morphogenesis of a branching epithelium	1
cellular process	1
response to hydroxyurea	1
cellular response to chemical stimulus	1
response to cisplatin	1
cellular response to oxygen-containing compound	1
response to bleomycin	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
positive regulation of DNA recombination	1
positive regulation of double-strand break repair	1
double-strand break repair	1
positive regulation of DNA repair	1
regulation of double-strand break repair	1
biological_process	1
nucleic acid binding	1

Protein interactions and networks

STRING

2314 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TIMELESS	TIPIN	Q9BVW5	999
TIMELESS	CLSPN	Q9HAW4	998
TIMELESS	CRY1	Q16526	996
TIMELESS	CRY2	Q49AN0	993
TIMELESS	WDHD1	O75717	978
TIMELESS	CHEK1	O14757	972
TIMELESS	CLOCK	O15516	949
TIMELESS	DDX11	Q96FC9	937
TIMELESS	BMAL1	O00327	897
TIMELESS	PER3	P56645	893
TIMELESS	NPAS2	Q99743	883
TIMELESS	MRC1	P22897	874
TIMELESS	PER2	O15055	872
TIMELESS	PARP1	P09874	870
TIMELESS	SMARCC1	Q92922	851

IntAct

61 interactions, top by confidence:

A	B	Type	Score
RPA2	RPA1	psi-mi:“MI:0914”(association)	0.960
RPA1	RPA2	psi-mi:“MI:0914”(association)	0.960
RPA3	RPA2	psi-mi:“MI:0914”(association)	0.930
GINS3	GINS1	psi-mi:“MI:0914”(association)	0.880
MCM2	MCM4	psi-mi:“MI:0914”(association)	0.830
TIPIN	TIMELESS	psi-mi:“MI:0407”(direct interaction)	0.730
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
TIPIN	TIMELESS	psi-mi:“MI:0915”(physical association)	0.730
TIPIN	MCM7	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
FAM9B	GEMIN2	psi-mi:“MI:0914”(association)	0.530
MCM7	CEP290	psi-mi:“MI:0914”(association)	0.530
H2BC26	PPM1G	psi-mi:“MI:0914”(association)	0.530
MCM3	MCM4	psi-mi:“MI:0914”(association)	0.530
MCM7	VPS26A	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TIMELESS	PARP1	psi-mi:“MI:0915”(physical association)	0.520
PARP1	TIMELESS	psi-mi:“MI:0915”(physical association)	0.520
PRIMPOL	RPA2	psi-mi:“MI:0914”(association)	0.510
TIMELESS	CRY2	psi-mi:“MI:0915”(physical association)	0.400
TIMELESS	CHEK1	psi-mi:“MI:0915”(physical association)	0.400
Tipin	RPA2	psi-mi:“MI:0915”(physical association)	0.400
Timeless	RPA2	psi-mi:“MI:0915”(physical association)	0.400
TIMELESS	DDX11	psi-mi:“MI:0915”(physical association)	0.400
TIMELESS	ZSCAN1	psi-mi:“MI:0915”(physical association)	0.370
PCBD1	TIMELESS	psi-mi:“MI:0915”(physical association)	0.370
TIMELESS	TF	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (185): TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), NASP (Co-fractionation), TIMELESS (Affinity Capture-MS), TIMELESS (Synthetic Growth Defect), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS), TIMELESS (Affinity Capture-MS)

ESM2 similar proteins: A0JNG7, A0JPF5, A0JPG1, A2VE70, B0V207, B1AY13, B4F766, F1QFR9, F1R2X6, O17482, O43156, P49021, P50851, Q05DH4, Q0P4Q0, Q15021, Q4S6U8, Q505K2, Q5PNP1, Q5RAW5, Q5SP90, Q5SSW2, Q5W0V3, Q5ZLW3, Q6DCP6, Q6IN85, Q6INN7, Q6NRP2, Q6P2K6, Q7RTS9, Q80TR8, Q80YR2, Q86V87, Q8CDM8, Q8CHY3, Q8IV36, Q8IY22, Q8K2Z4, Q8NFP9, Q8R1F6

Diamond homologs: Q9R1X4, Q9UNS1, Q9Z2Y1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NR3C1	“up-regulates quantity by expression”	TIMELESS	“transcriptional regulation”
TIMELESS	“up-regulates activity”	CRY1	binding
TIMELESS	“up-regulates activity”	CHEK1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 74 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of ATR in response to replication stress	10	63.9×	6e-14
Activation of the pre-replicative complex	8	55.5×	8e-11
DNA Replication Pre-Initiation	5	33.8×	1e-05
Synthesis of DNA	5	32.0×	1e-05
Presynaptic phase of homologous DNA pairing and strand exchange	5	28.9×	2e-05
DNA Replication	5	25.3×	3e-05
G1/S Transition	5	24.8×	3e-05
Mitotic G1 phase and G1/S transition	5	19.6×	8e-05

GO biological processes:

GO term	Partners	Fold	FDR
DNA replication	13	34.1×	2e-14
telomere maintenance	5	21.2×	2e-04
double-strand break repair	5	16.1×	5e-04
nucleosome assembly	6	13.4×	2e-04
DNA repair	9	9.1×	4e-05
DNA damage response	10	8.5×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

215 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	164
Likely benign	17
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1702937	NM_003920.5(TIMELESS):c.3241C>T (p.Arg1081Ter)	Pathogenic

SpliceAI

3902 predictions. Top by Δscore:

Variant	Effect	Δscore
12:56417930:T:TA	donor_gain	1.0000
12:56418004:TTCCT:T	acceptor_gain	1.0000
12:56418005:TCCT:T	acceptor_gain	1.0000
12:56418006:CCTC:C	acceptor_gain	1.0000
12:56418007:CT:C	acceptor_gain	1.0000
12:56418008:TC:T	acceptor_loss	1.0000
12:56418009:C:CC	acceptor_gain	1.0000
12:56418009:C:T	acceptor_loss	1.0000
12:56418010:T:A	acceptor_loss	1.0000
12:56418012:C:CT	acceptor_gain	1.0000
12:56418013:A:T	acceptor_gain	1.0000
12:56418014:A:AC	acceptor_gain	1.0000
12:56418018:CCA:C	acceptor_gain	1.0000
12:56418019:C:T	acceptor_gain	1.0000
12:56418019:CA:C	acceptor_gain	1.0000
12:56418020:A:C	acceptor_gain	1.0000
12:56418020:A:T	acceptor_gain	1.0000
12:56418132:AC:A	donor_gain	1.0000
12:56418133:CC:C	donor_gain	1.0000
12:56420564:TTTAC:T	donor_loss	1.0000
12:56420565:TTACC:T	donor_loss	1.0000
12:56420566:TA:T	donor_loss	1.0000
12:56420567:ACC:A	donor_loss	1.0000
12:56420961:ACCTT:A	donor_gain	1.0000
12:56420962:CCTTC:C	donor_gain	1.0000
12:56420965:T:TA	donor_gain	1.0000
12:56421013:C:A	donor_gain	1.0000
12:56421049:T:TA	donor_gain	1.0000
12:56421130:TTTGG:T	acceptor_gain	1.0000
12:56421131:TTGG:T	acceptor_gain	1.0000

AlphaMissense

7919 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56421787:A:G	W889R	0.998
12:56421787:A:T	W889R	0.998
12:56433650:A:G	L85P	0.997
12:56433911:A:G	L38P	0.997
12:56434118:C:T	G18E	0.997
12:56421785:C:A	W889C	0.996
12:56421785:C:G	W889C	0.996
12:56428309:A:G	L502P	0.996
12:56433084:C:G	R158P	0.996
12:56433066:C:A	R164I	0.995
12:56421762:A:G	L897P	0.994
12:56428943:A:G	L415P	0.994
12:56430956:A:C	F278L	0.994
12:56430956:A:T	F278L	0.994
12:56430958:A:G	F278L	0.994
12:56433066:C:G	R164T	0.994
12:56433830:A:G	L65P	0.994
12:56434119:C:G	G18R	0.994
12:56434119:C:T	G18R	0.994
12:56428620:A:G	L446P	0.993
12:56433062:A:C	N165K	0.993
12:56433062:A:T	N165K	0.993
12:56433860:A:G	L55P	0.993
12:56434119:C:A	G18W	0.993
12:56421427:A:G	L931P	0.992
12:56423887:A:G	W626R	0.992
12:56423887:A:T	W626R	0.992
12:56428638:A:G	L440P	0.992
12:56421941:A:G	L867P	0.991
12:56433065:T:A	R164S	0.991

dbSNP variants (sampled 300 via entrez): RS1000100136 (12:56425207 A>G), RS1000191113 (12:56439029 G>A,C), RS1000203409 (12:56448523 G>C), RS1000243332 (12:56451400 G>A,T), RS1000357580 (12:56442493 T>C), RS1000400350 (12:56430621 C>A), RS1000475527 (12:56416621 T>C), RS1000508977 (12:56438548 G>A), RS1000533920 (12:56419926 G>C), RS1000586290 (12:56420361 G>T), RS1000604889 (12:56448328 C>A,T), RS1000685806 (12:56446791 T>A,C), RS1000729591 (12:56434280 G>C), RS1000742043 (12:56416336 G>A), RS1000898981 (12:56431815 C>A,T)

Disease associations

OMIM: gene MIM:603887 | disease phenotypes: MIM:620015

GenCC curated gene-disease

Mondo (1): advance sleep phase syndrome, familial, 4 (MONDO:0031044)

Orphanet (0):

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0031873	Early chronotype

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001538_18	Immune reponse to smallpox (secreted IFN-alpha)	6.000000e-10
GCST002115_16	Axial length	4.000000e-07
GCST010002_217	Refractive error	6.000000e-174

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004645	response to vaccine
EFO:0004873	cytokine measurement
EFO:0005318	axial length measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Valproic Acid	decreases expression, affects expression, affects cotreatment	5
Resveratrol	affects cotreatment, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Cisplatin	affects cotreatment, increases expression	2
Estradiol	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
geraniol	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cyanoginosin LR	affects binding, decreases reaction, increases reaction, decreases expression	1
phenethyl isothiocyanate	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
incobotulinumtoxinA	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.