UniProtKB - Q9UNS1 (TIM_HUMAN)
Protein timeless homolog
TIMELESS
Functioni
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 (PubMed:9856465, PubMed:17141802, PubMed:17296725, PubMed:23418588, PubMed:26344098).
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 (PubMed:17141802, PubMed:17296725).
TIMELESS promotes TIPIN nuclear localization (PubMed:17141802, PubMed:17296725).
Involved in cell survival after DNA damage or replication stress by promoting DNA repair (PubMed:17141802, PubMed:17296725, PubMed:26344098, PubMed:30356214).
In response to double-strand breaks (DSBs), accumulates at DNA damage sites and promotes homologous recombination repair via its interaction with PARP1 (PubMed:26344098, PubMed:30356214).
May be specifically required for the ATR-CHEK1 pathway in the replication checkpoint induced by hydroxyurea or ultraviolet light (PubMed:15798197).
Involved in the determination of period length and in the DNA damage-dependent phase advancing of the circadian clock (PubMed:23418588).
Negatively regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1 possibly via translocation of PER1 into the nucleus (PubMed:9856465).
May also play an important role in epithelial cell morphogenesis and formation of branching tubules (By similarity).
By similarity7 PublicationsGO - Molecular functioni
- DNA binding Source: GO_Central
- identical protein binding Source: Ensembl
GO - Biological processi
- branching morphogenesis of an epithelial tube Source: Ensembl
- cell cycle phase transition Source: BHF-UCL
- cell division Source: UniProtKB-KW
- cellular response to bleomycin Source: UniProtKB
- cellular response to cisplatin Source: UniProtKB
- cellular response to DNA damage stimulus Source: UniProtKB
- cellular response to hydroxyurea Source: UniProtKB
- circadian rhythm Source: UniProtKB
- detection of abiotic stimulus Source: ProtInc
- DNA repair Source: GO_Central
- DNA replication checkpoint signaling Source: GO_Central
- lung development Source: Ensembl
- morphogenesis of an epithelium Source: UniProtKB
- negative regulation of transcription, DNA-templated Source: UniProtKB
- negative regulation of transcription by RNA polymerase II Source: Ensembl
- positive regulation of double-strand break repair Source: UniProtKB
- positive regulation of double-strand break repair via homologous recombination Source: UniProtKB
- regulation of circadian rhythm Source: UniProtKB
- replication fork arrest Source: GO_Central
- replication fork protection Source: GO_Central
Keywordsi
Molecular function | Developmental protein |
Biological process | Biological rhythms, Cell cycle, Cell division, DNA damage, DNA repair, Mitosis, Transcription, Transcription regulation |
Enzyme and pathway databases
PathwayCommonsi | Q9UNS1 |
Reactomei | R-HSA-5693607, Processing of DNA double-strand break ends |
SignaLinki | Q9UNS1 |
Names & Taxonomyi
Protein namesi | Recommended name: Protein timeless homologShort name: hTIM |
Gene namesi | |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:11813, TIMELESS |
MIMi | 603887, gene |
neXtProti | NX_Q9UNS1 |
VEuPathDBi | HostDB:ENSG00000111602 |
Subcellular locationi
Nucleus
- Nucleus 1 Publication
Other locations
- Chromosome 1 Publication
Note: In response to double-strand breaks (DSBs), accumulates at DNA damage sites via its interaction with PARP1.1 Publication
Nucleus
- nucleoplasm Source: HPA
- nucleus Source: HGNC-UCL
- replication fork protection complex Source: GO_Central
Other locations
- chromatin Source: HGNC-UCL
- site of double-strand break Source: UniProtKB
Keywords - Cellular componenti
Chromosome, NucleusPathology & Biotechi
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 1081 | R → G: Abolishes interaction with PARP1. 1 Publication | 1 |
Organism-specific databases
DisGeNETi | 8914 |
OpenTargetsi | ENSG00000111602 |
PharmGKBi | PA36520 |
Miscellaneous databases
Pharosi | Q9UNS1, Tbio |
Genetic variation databases
BioMutai | TIMELESS |
DMDMi | 296452931 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000072538 | 1 – 1208 | Protein timeless homologAdd BLAST | 1208 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 281 | PhosphoserineCombined sources | 1 | |
Modified residuei | 1074 | PhosphoserineCombined sources | 1 | |
Modified residuei | 1087 | PhosphoserineCombined sources | 1 | |
Modified residuei | 1089 | PhosphothreonineCombined sources | 1 | |
Modified residuei | 1149 | PhosphoserineCombined sources | 1 | |
Modified residuei | 1173 | PhosphoserineCombined sources | 1 |
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | Q9UNS1 |
jPOSTi | Q9UNS1 |
MassIVEi | Q9UNS1 |
MaxQBi | Q9UNS1 |
PaxDbi | Q9UNS1 |
PeptideAtlasi | Q9UNS1 |
PRIDEi | Q9UNS1 |
ProteomicsDBi | 85326 [Q9UNS1-1] 85327 [Q9UNS1-2] |
PTM databases
iPTMneti | Q9UNS1 |
PhosphoSitePlusi | Q9UNS1 |
Expressioni
Tissue specificityi
Inductioni
Gene expression databases
Bgeei | ENSG00000111602, Expressed in ventricular zone and 181 other tissues |
Genevisiblei | Q9UNS1, HS |
Organism-specific databases
HPAi | ENSG00000111602, Low tissue specificity |
Interactioni
Subunit structurei
Homodimer or homomultimer (By similarity).
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 (PubMed:9856465).
Interacts directly with PER2; the interaction with PER2 is via its second PAS domain (By similarity).
Interacts directly with PER1 and PER3 (By similarity).
Interacts with CRY2, CHEK1, ATR and ATRIP (PubMed:15798197).
Interacts with CRY1 (By similarity).
Interacts with CLSPN (PubMed:17141802).
Interacts with TIPIN (PubMed:17102137, PubMed:17116885, PubMed:17296725).
Interacts with DDX11; this interaction increases recruitment of both proteins onto chromatin in response to replication stress induction by hydroxyurea (PubMed:20124417, PubMed:26503245).
Interacts with PARP1; interaction is direct and independent of poly-ADP-ribose (PubMed:26344098, PubMed:30356214).
By similarity10 PublicationsBinary interactionsi
Q9UNS1
With | #Exp. | IntAct |
---|---|---|
CHEK1 [O14757] | 2 | EBI-2212315,EBI-974488 |
GO - Molecular functioni
- identical protein binding Source: Ensembl
Protein-protein interaction databases
BioGRIDi | 114428, 111 interactors |
DIPi | DIP-47395N |
IntActi | Q9UNS1, 29 interactors |
MINTi | Q9UNS1 |
STRINGi | 9606.ENSP00000450607 |
Miscellaneous databases
RNActi | Q9UNS1, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | Q9UNS1 |
SMRi | Q9UNS1 |
ModBasei | Search... |
PDBe-KBi | Search... |
Family & Domainsi
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 1 – 309 | Required for homodimerization and for interaction with CRY1 and CHEK1By similarityAdd BLAST | 309 | |
Regioni | 655 – 679 | DisorderedSequence analysisAdd BLAST | 25 | |
Regioni | 971 – 994 | DisorderedSequence analysisAdd BLAST | 24 | |
Regioni | 1000 – 1098 | Interaction with PARP11 PublicationAdd BLAST | 99 | |
Regioni | 1082 – 1208 | Required for nuclear localizationBy similarityAdd BLAST | 127 | |
Regioni | 1091 – 1131 | DisorderedSequence analysisAdd BLAST | 41 | |
Regioni | 1143 – 1208 | DisorderedSequence analysisAdd BLAST | 66 |
Compositional bias
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Compositional biasi | 664 – 679 | Acidic residuesSequence analysisAdd BLAST | 16 | |
Compositional biasi | 971 – 991 | Acidic residuesSequence analysisAdd BLAST | 21 | |
Compositional biasi | 1092 – 1106 | Polar residuesSequence analysisAdd BLAST | 15 | |
Compositional biasi | 1117 – 1131 | Basic and acidic residuesSequence analysisAdd BLAST | 15 | |
Compositional biasi | 1145 – 1173 | Basic and acidic residuesSequence analysisAdd BLAST | 29 |
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG1974, Eukaryota |
GeneTreei | ENSGT01040000240636 |
HOGENOMi | CLU_003493_0_0_1 |
InParanoidi | Q9UNS1 |
OMAi | QGPEECG |
OrthoDBi | 839367at2759 |
PhylomeDBi | Q9UNS1 |
TreeFami | TF312802 |
Family and domain databases
InterProi | View protein in InterPro IPR044998, Timeless IPR007725, TIMELESS_C IPR006906, Timeless_N |
PANTHERi | PTHR22940, PTHR22940, 1 hit |
Pfami | View protein in Pfam PF04821, TIMELESS, 1 hit PF05029, TIMELESS_C, 1 hit |
s (2)i Sequence
Sequence statusi: Complete.
This entry describes 2 produced by isoformsialternative splicing. AlignAdd to basketThis isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD
60 70 80 90 100
VRQQLGAAQI LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL
110 120 130 140 150
PKEPSFRHHF LQVLTYLQAY KEAFASEKAF GVLSETLYEL LQLGWEERQE
160 170 180 190 200
EDNLLIERIL LLVRNILHVP ADLDQEKKID DDASAHDQLL WAIHLSGLDD
210 220 230 240 250
LLLFLASSSA EEQWSLHVLE IVSLMFRDQN PEQLAGVGQG RLAQERSADF
260 270 280 290 300
AELEVLRQRE MAEKKTRALQ RGNRHSRFGG SYIVQGLKSI GERDLIFHKG
310 320 330 340 350
LHNLRNYSSD LGKQPKKVPK RRQAARELSI QRRSALNVRL FLRDFCSEFL
360 370 380 390 400
ENCYNRLMGS VKDHLLREKA QQHDETYYMW ALAFFMAFNR AASFRPGLVS
410 420 430 440 450
ETLSVRTFHF IEQNLTNYYE MMLTDRKEAA SWARRMHLAL KAYQELLATV
460 470 480 490 500
NEMDISPDEA VRESSRIIKN NIFYVMEYRE LFLALFRKFD ERCQPRSFLR
510 520 530 540 550
DLVETTHLFL KMLERFCRSR GNLVVQNKQK KRRKKKKKVL DQAIVSGNVP
560 570 580 590 600
SSPEEVEAVW PALAEQLQCC AQNSELSMDS VVPFDAASEV PVEEQRAEAM
610 620 630 640 650
VRIQDCLLAG QAPQALTLLR SAREVWPEGD VFGSQDISPE EEIQLLKQIL
660 670 680 690 700
SAPLPRQQGP EERGAEEEEE EEEEEEEELQ VVQVSEKEFN FLDYLKRFAC
710 720 730 740 750
STVVRAYVLL LRSYQQNSAH TNHCIVKMLH RLAHDLKMEA LLFQLSVFCL
760 770 780 790 800
FNRLLSDPAA GAYKELVTFA KYILGKFFAL AAVNQKAFVE LLFWKNTAVV
810 820 830 840 850
REMTEGYGSL DDRSSSRRAP TWSPEEEAHL RELYLANKDV EGQDVVEAIL
860 870 880 890 900
AHLNTVPRTR KQIIHHLVQM GLADSVKDFQ RKGTHIVLWT GDQELELQRL
910 920 930 940 950
FEEFRDSDDV LGHIMKNITA KRSRARIVDK LLALGLVAER RELYKKRQKK
960 970 980 990 1000
LASSILPNGA ESLKDFCQED LEEEENLPEE DSEEEEEGGS EAEQVQGSLV
1010 1020 1030 1040 1050
LSNENLGQSL HQEGFSIPLL WLQNCLIRAA DDREEDGCSQ AVPLVPLTEE
1060 1070 1080 1090 1100
NEEAMENEQF QQLLRKLGVR PPASGQETFW RIPAKLSPTQ LRRAAASLSQ
1110 1120 1130 1140 1150
PEEEQKLQPE LQPKVPGEQG SDEEHCKEHR AQALRALLLA HKKKAGLASP
1160 1170 1180 1190 1200
EEEDAVGKEP LKAAPKKRQL LDSDEEQEED EGRNRAPELG APGIQKKKRY
QIEDDEDD
Sequence cautioni
Natural variant
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Natural variantiVAR_047879 | 129 | A → S1 PublicationCorresponds to variant dbSNP:rs72478986EnsemblClinVar. | 1 | |
Natural variantiVAR_036435 | 429 | A → D in a breast cancer sample; somatic mutation. 1 Publication | 1 | |
Natural variantiVAR_021483 | 455 | I → L3 PublicationsCorresponds to variant dbSNP:rs774027Ensembl. | 1 | |
Natural variantiVAR_047880 | 471 | N → S1 PublicationCorresponds to variant dbSNP:rs72478993Ensembl. | 1 | |
Natural variantiVAR_021484 | 831 | R → Q3 PublicationsCorresponds to variant dbSNP:rs774047Ensembl. | 1 | |
Natural variantiVAR_047881 | 870 | M → V1 PublicationCorresponds to variant dbSNP:rs61733875Ensembl. | 1 | |
Natural variantiVAR_047882 | 922 | R → H1 PublicationCorresponds to variant dbSNP:rs72478999Ensembl. | 1 | |
Natural variantiVAR_047883 | 924 | R → W1 PublicationCorresponds to variant dbSNP:rs72479000Ensembl. | 1 | |
Natural variantiVAR_036436 | 1008 | Q → E in a breast cancer sample; somatic mutation. 1 PublicationCorresponds to variant dbSNP:rs151188513Ensembl. | 1 | |
Natural variantiVAR_047884 | 1017 | I → T1 PublicationCorresponds to variant dbSNP:rs61376834Ensembl. | 1 | |
Natural variantiVAR_021485 | 1018 | P → L2 PublicationsCorresponds to variant dbSNP:rs2291739Ensembl. | 1 |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_051693 | 177 | Missing in isoform 2. 2 Publications | 1 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AB015597 mRNA Translation: BAA36499.1 AF098162 mRNA Translation: AAC80011.1 EU627094 Genomic DNA Translation: ACD11488.1 AC024884 Genomic DNA No translation available. BC039842 mRNA Translation: AAH39842.1 Sequence problems. BC050557 mRNA Translation: AAH50557.1 |
CCDSi | CCDS81699.1 [Q9UNS1-2] CCDS8918.1 [Q9UNS1-1] |
RefSeqi | NP_001317224.1, NM_001330295.1 [Q9UNS1-2] NP_003911.2, NM_003920.4 [Q9UNS1-1] |
Genome annotation databases
Ensembli | ENST00000229201.4; ENSP00000229201.4; ENSG00000111602.12 [Q9UNS1-2] ENST00000553532.6; ENSP00000450607.1; ENSG00000111602.12 |
GeneIDi | 8914 |
KEGGi | hsa:8914 |
MANE-Selecti | ENST00000553532.6; ENSP00000450607.1; NM_003920.5; NP_003911.2 |
UCSCi | uc001slf.3, human [Q9UNS1-1] |
Keywords - Coding sequence diversityi
Alternative splicingSimilar proteinsi
Cross-referencesi
Web resourcesi
NIEHS-SNPs |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | AB015597 mRNA Translation: BAA36499.1 AF098162 mRNA Translation: AAC80011.1 EU627094 Genomic DNA Translation: ACD11488.1 AC024884 Genomic DNA No translation available. BC039842 mRNA Translation: AAH39842.1 Sequence problems. BC050557 mRNA Translation: AAH50557.1 |
CCDSi | CCDS81699.1 [Q9UNS1-2] CCDS8918.1 [Q9UNS1-1] |
RefSeqi | NP_001317224.1, NM_001330295.1 [Q9UNS1-2] NP_003911.2, NM_003920.4 [Q9UNS1-1] |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
4XHT | X-ray | 1.65 | A/B/C/D | 1000-1098 | [»] | |
4XHU | X-ray | 2.09 | B/D | 1000-1098 | [»] | |
4XHW | X-ray | 2.85 | A/B/C/D | 1000-1098 | [»] | |
5MQI | X-ray | 1.85 | A | 1-238 | [»] | |
A | 331-463 | [»] | ||||
6T9Q | X-ray | 1.15 | A | 883-947 | [»] | |
6TAZ | NMR | - | B | 816-954 | [»] | |
7PFO | electron microscopy | 3.20 | K | 1-1208 | [»] | |
7PLO | electron microscopy | 2.80 | K | 1-1208 | [»] | |
AlphaFoldDBi | Q9UNS1 | |||||
SMRi | Q9UNS1 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 114428, 111 interactors |
DIPi | DIP-47395N |
IntActi | Q9UNS1, 29 interactors |
MINTi | Q9UNS1 |
STRINGi | 9606.ENSP00000450607 |
PTM databases
iPTMneti | Q9UNS1 |
PhosphoSitePlusi | Q9UNS1 |
Genetic variation databases
BioMutai | TIMELESS |
DMDMi | 296452931 |
Proteomic databases
EPDi | Q9UNS1 |
jPOSTi | Q9UNS1 |
MassIVEi | Q9UNS1 |
MaxQBi | Q9UNS1 |
PaxDbi | Q9UNS1 |
PeptideAtlasi | Q9UNS1 |
PRIDEi | Q9UNS1 |
ProteomicsDBi | 85326 [Q9UNS1-1] 85327 [Q9UNS1-2] |
Protocols and materials databases
Antibodypediai | 15850, 204 antibodies from 31 providers |
DNASUi | 8914 |
Genome annotation databases
Ensembli | ENST00000229201.4; ENSP00000229201.4; ENSG00000111602.12 [Q9UNS1-2] ENST00000553532.6; ENSP00000450607.1; ENSG00000111602.12 |
GeneIDi | 8914 |
KEGGi | hsa:8914 |
MANE-Selecti | ENST00000553532.6; ENSP00000450607.1; NM_003920.5; NP_003911.2 |
UCSCi | uc001slf.3, human [Q9UNS1-1] |
Organism-specific databases
CTDi | 8914 |
DisGeNETi | 8914 |
GeneCardsi | TIMELESS |
HGNCi | HGNC:11813, TIMELESS |
HPAi | ENSG00000111602, Low tissue specificity |
MIMi | 603887, gene |
neXtProti | NX_Q9UNS1 |
OpenTargetsi | ENSG00000111602 |
PharmGKBi | PA36520 |
VEuPathDBi | HostDB:ENSG00000111602 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG1974, Eukaryota |
GeneTreei | ENSGT01040000240636 |
HOGENOMi | CLU_003493_0_0_1 |
InParanoidi | Q9UNS1 |
OMAi | QGPEECG |
OrthoDBi | 839367at2759 |
PhylomeDBi | Q9UNS1 |
TreeFami | TF312802 |
Enzyme and pathway databases
PathwayCommonsi | Q9UNS1 |
Reactomei | R-HSA-5693607, Processing of DNA double-strand break ends |
SignaLinki | Q9UNS1 |
Miscellaneous databases
BioGRID-ORCSi | 8914, 723 hits in 1064 CRISPR screens |
ChiTaRSi | TIMELESS, human |
GenomeRNAii | 8914 |
Pharosi | Q9UNS1, Tbio |
PROi | PR:Q9UNS1 |
RNActi | Q9UNS1, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000111602, Expressed in ventricular zone and 181 other tissues |
Genevisiblei | Q9UNS1, HS |
Family and domain databases
InterProi | View protein in InterPro IPR044998, Timeless IPR007725, TIMELESS_C IPR006906, Timeless_N |
PANTHERi | PTHR22940, PTHR22940, 1 hit |
Pfami | View protein in Pfam PF04821, TIMELESS, 1 hit PF05029, TIMELESS_C, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | TIM_HUMAN | |
Accessioni | Q9UNS1Primary (citable) accession number: Q9UNS1 Secondary accession number(s): B2ZAV0 Q8IWH3 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | March 15, 2005 |
Last sequence update: | May 18, 2010 | |
Last modified: | May 25, 2022 | |
This is version 176 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human chromosome 12
Human chromosome 12: entries, gene names and cross-references to MIM - Human entries with genetic variants
List of human entries with genetic variants - Human variants curated from literature reports
Index of human variants curated from literature reports - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references - SIMILARITY comments
Index of protein domains and families