TIM_HUMAN
ID TIM_HUMAN Reviewed; 1208 AA.
AC Q9UNS1; B2ZAV0; O94802; Q86VM1; Q8IWH3;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 18-MAY-2010, sequence version 2.
DT 03-AUG-2022, entry version 177.
DE RecName: Full=Protein timeless homolog;
DE Short=hTIM;
GN Name=TIMELESS {ECO:0000312|EMBL:AAH50557.1};
GN Synonyms=TIM {ECO:0000303|PubMed:9856465},
GN TIM1 {ECO:0000303|PubMed:9891984}, TIMELESS1 {ECO:0000303|PubMed:9891984};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1] {ECO:0000312|EMBL:BAA36499.1}
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, AND VARIANT
RP LEU-455.
RC TISSUE=Brain {ECO:0000312|EMBL:BAA36499.1};
RX PubMed=9891984; DOI=10.1016/s0014-5793(98)01597-x;
RA Koike N., Hida A., Numano R., Hirose M., Sakaki Y., Tei H.;
RT "Identification of the mammalian homologues of the Drosophila timeless
RT gene, Timeless1.";
RL FEBS Lett. 441:427-431(1998).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), FUNCTION, TISSUE
RP SPECIFICITY, AND VARIANTS LEU-455 AND GLN-831.
RC TISSUE=Placenta;
RX PubMed=9856465; DOI=10.1016/s0896-6273(00)80627-3;
RA Sangoram A.M., Saez L., Antoch M.P., Gekakis N., Staknis D., Whiteley A.,
RA Fruechte E.M., Vitaterna M.H., Shimomura K., King D.P., Young M.W.,
RA Weitz C.J., Takahashi J.S.;
RT "Mammalian circadian autoregulatory loop: a timeless ortholog and mPer1
RT interact and negatively regulate CLOCK-ARTNL/BMAL1-induced transcription.";
RL Neuron 21:1101-1113(1998).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-129; LEU-455; SER-471;
RP GLN-831; VAL-870; HIS-922; TRP-924; THR-1017 AND LEU-1018.
RG NIEHS SNPs program;
RL Submitted (APR-2008) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M., Kovar-Smith C.,
RA Lewis L.R., Lozado R.J., Metzker M.L., Milosavljevic A., Miner G.R.,
RA Montgomery K.T., Morgan M.B., Nazareth L.V., Scott G., Sodergren E.,
RA Song X.-Z., Steffen D., Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y.,
RA Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G.,
RA Chen Z., Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H.,
RA Draper H., Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S.,
RA Kelly S.H., Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M.,
RA Nguyen B.-V., Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H.,
RA Santibanez J., Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q.,
RA Williams G.A., Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V.,
RA Bailey M., Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E.,
RA Burkett C.E., Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M., Dathorne S.R.,
RA David R., Davis C.M., Davy-Carroll L., Deshazo D.R., Donlin J.E.,
RA D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J., Escotto M., Flagg N.,
RA Forbes L.D., Gabisi A.M., Garza M., Hamilton C., Henderson N.,
RA Hernandez O., Hines S., Hogues M.E., Huang M., Idlebird D.G., Johnson R.,
RA Jolivet A., Jones S., Kagan R., King L.M., Leal B., Lebow H., Lee S.,
RA LeVan J.M., Lewis L.C., London P., Lorensuhewa L.M., Loulseged H.,
RA Lovett D.A., Lucier A., Lucier R.L., Ma J., Madu R.C., Mapua P.,
RA Martindale A.D., Martinez E., Massey E., Mawhiney S., Meador M.G.,
RA Mendez S., Mercado C., Mercado I.C., Merritt C.E., Miner Z.L., Minja E.,
RA Mitchell T., Mohabbat F., Mohabbat K., Montgomery B., Moore N., Morris S.,
RA Munidasa M., Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O.,
RA Nwokenkwo S., Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D., Trejos Z.Y.,
RA Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I., Vera V.A.,
RA Villasana D.M., Wang L., Ward-Moore S., Warren J.T., Wei X., White F.,
RA Williamson A.L., Wleczyk R., Wooden H.S., Wooden S.H., Yen J., Yoon L.,
RA Yoon V., Zorrilla S.E., Nelson D., Kucherlapati R., Weinstock G.,
RA Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANTS
RP GLN-831 AND LEU-1018.
RC TISSUE=Duodenum {ECO:0000312|EMBL:AAH50557.1}, and
RC Skin {ECO:0000312|EMBL:AAH39842.1};
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, INTERACTION WITH ATR; ATRIP; CHEK1 AND CRY2, AND INDUCTION.
RX PubMed=15798197; DOI=10.1128/mcb.25.8.3109-3116.2005;
RA Uensal-Kacmaz K., Mullen T.E., Kaufmann W.K., Sancar A.;
RT "Coupling of human circadian and cell cycles by the timeless protein.";
RL Mol. Cell. Biol. 25:3109-3116(2005).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [8]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1173, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=16964243; DOI=10.1038/nbt1240;
RA Beausoleil S.A., Villen J., Gerber S.A., Rush J., Gygi S.P.;
RT "A probability-based approach for high-throughput protein phosphorylation
RT analysis and site localization.";
RL Nat. Biotechnol. 24:1285-1292(2006).
RN [9]
RP INTERACTION WITH TIPIN.
RX PubMed=17116885; DOI=10.1073/pnas.0609251103;
RA Chou D.M., Elledge S.J.;
RT "Tipin and Timeless form a mutually protective complex required for
RT genotoxic stress resistance and checkpoint function.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:18143-18147(2006).
RN [10]
RP INTERACTION WITH TIPIN.
RX PubMed=17102137; DOI=10.1074/jbc.m605596200;
RA Yoshizawa-Sugata N., Masai H.;
RT "Human Tim/Timeless-interacting protein, Tipin, is required for efficient
RT progression of S phase and DNA replication checkpoint.";
RL J. Biol. Chem. 282:2729-2740(2007).
RN [11]
RP SUBCELLULAR LOCATION, INTERACTION WITH CLSPN, AND FUNCTION.
RX PubMed=17141802; DOI=10.1016/j.jmb.2006.10.097;
RA Gotter A.L., Suppa C., Emanuel B.S.;
RT "Mammalian TIMELESS and Tipin are evolutionarily conserved replication
RT fork-associated factors.";
RL J. Mol. Biol. 366:36-52(2007).
RN [12]
RP INTERACTION WITH TIPIN, AND FUNCTION.
RX PubMed=17296725; DOI=10.1128/mcb.02190-06;
RA Uensal-Kacmaz K., Chastain P.D., Qu P.-P., Minoo P., Cordeiro-Stone M.,
RA Sancar A., Kaufmann W.K.;
RT "The human Tim/Tipin complex coordinates an Intra-S checkpoint response to
RT UV that slows replication fork displacement.";
RL Mol. Cell. Biol. 27:3131-3142(2007).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [14]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J., Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in a
RT refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [15]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [16]
RP REVIEW.
RX PubMed=20139726; DOI=10.4161/cc.9.4.10676;
RA McFarlane R.J., Mian S., Dalgaard J.Z.;
RT "The many facets of the Tim-Tipin protein families' roles in chromosome
RT biology.";
RL Cell Cycle 9:700-705(2010).
RN [17]
RP INTERACTION WITH DDX11.
RX PubMed=20124417; DOI=10.1242/jcs.057984;
RA Leman A.R., Noguchi C., Lee C.Y., Noguchi E.;
RT "Human Timeless and Tipin stabilize replication forks and facilitate
RT sister-chromatid cohesion.";
RL J. Cell Sci. 123:660-670(2010).
RN [18]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [19]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [20]
RP REVIEW.
RX PubMed=21670590; DOI=10.4161/cc.10.14.15853;
RA Diaz-Martinez L.A., Clarke D.J.;
RT "Timeless makes some time for itself.";
RL Cell Cycle 10:2254-2254(2011).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1149 AND SER-1173, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [22]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-281; SER-1074; SER-1087;
RP THR-1089; SER-1149 AND SER-1173, AND IDENTIFICATION BY MASS SPECTROMETRY
RP [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [23]
RP FUNCTION.
RX PubMed=23418588; DOI=10.1371/journal.pone.0056623;
RA Engelen E., Janssens R.C., Yagita K., Smits V.A., van der Horst G.T.,
RA Tamanini F.;
RT "Mammalian TIMELESS is involved in period determination and DNA damage-
RT dependent phase advancing of the circadian clock.";
RL PLoS ONE 8:E56623-E56623(2013).
RN [24]
RP INTERACTION WITH DDX11.
RX PubMed=26503245; DOI=10.1093/nar/gkv1112;
RA Cali F., Bharti S.K., Di Perna R., Brosh R.M. Jr., Pisani F.M.;
RT "Tim/Timeless, a member of the replication fork protection complex,
RT operates with the Warsaw breakage syndrome DNA helicase DDX11 in the same
RT fork recovery pathway.";
RL Nucleic Acids Res. 44:705-717(2016).
RN [25]
RP FUNCTION, AND INTERACTION WITH PARP1.
RX PubMed=30356214; DOI=10.1038/s41586-018-0629-6;
RA Liu H., Zhang H., Wu X., Ma D., Wu J., Wang L., Jiang Y., Fei Y., Zhu C.,
RA Tan R., Jungblut P., Pei G., Dorhoi A., Yan Q., Zhang F., Zheng R., Liu S.,
RA Liang H., Liu Z., Yang H., Chen J., Wang P., Tang T., Peng W., Hu Z.,
RA Xu Z., Huang X., Wang J., Li H., Zhou Y., Liu F., Yan D., Kaufmann S.H.E.,
RA Chen C., Mao Z., Ge B.;
RT "Nuclear cGAS suppresses DNA repair and promotes tumorigenesis.";
RL Nature 563:131-136(2018).
RN [26] {ECO:0007744|PDB:4XHT, ECO:0007744|PDB:4XHU, ECO:0007744|PDB:4XHW}
RP X-RAY CRYSTALLOGRAPHY (1.65 ANGSTROMS) OF 1000-1098 IN COMPLEX WITH PARP1,
RP FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH PARP1, AND MUTAGENESIS OF
RP ARG-1081.
RX PubMed=26344098; DOI=10.1016/j.molcel.2015.07.031;
RA Xie S., Mortusewicz O., Ma H.T., Herr P., Poon R.Y., Helleday T., Qian C.;
RT "Timeless interacts with PARP-1 to promote homologous recombination
RT repair.";
RL Mol. Cell 60:163-176(2015).
RN [27]
RP VARIANTS [LARGE SCALE ANALYSIS] ASP-429 AND GLU-1008.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P.,
RA Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V.,
RA Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H.,
RA Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W.,
RA Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal cancers.";
RL Science 314:268-274(2006).
CC -!- FUNCTION: Plays an important role in the control of DNA replication,
CC maintenance of replication fork stability, maintenance of genome
CC stability throughout normal DNA replication, DNA repair and in the
CC regulation of the circadian clock (PubMed:9856465, PubMed:17141802,
CC PubMed:17296725, PubMed:23418588, PubMed:26344098). Required to
CC stabilize replication forks during DNA replication by forming a complex
CC with TIPIN: this complex regulates DNA replication processes under both
CC normal and stress conditions, stabilizes replication forks and
CC influences both CHEK1 phosphorylation and the intra-S phase checkpoint
CC in response to genotoxic stress (PubMed:17141802, PubMed:17296725).
CC TIMELESS promotes TIPIN nuclear localization (PubMed:17141802,
CC PubMed:17296725). Involved in cell survival after DNA damage or
CC replication stress by promoting DNA repair (PubMed:17141802,
CC PubMed:17296725, PubMed:26344098, PubMed:30356214). In response to
CC double-strand breaks (DSBs), accumulates at DNA damage sites and
CC promotes homologous recombination repair via its interaction with PARP1
CC (PubMed:26344098, PubMed:30356214). May be specifically required for
CC the ATR-CHEK1 pathway in the replication checkpoint induced by
CC hydroxyurea or ultraviolet light (PubMed:15798197). Involved in the
CC determination of period length and in the DNA damage-dependent phase
CC advancing of the circadian clock (PubMed:23418588). Negatively
CC regulates CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation
CC of PER1 possibly via translocation of PER1 into the nucleus
CC (PubMed:9856465). May also play an important role in epithelial cell
CC morphogenesis and formation of branching tubules (By similarity).
CC {ECO:0000250|UniProtKB:Q9R1X4, ECO:0000269|PubMed:15798197,
CC ECO:0000269|PubMed:17141802, ECO:0000269|PubMed:17296725,
CC ECO:0000269|PubMed:23418588, ECO:0000269|PubMed:26344098,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:9856465}.
CC -!- SUBUNIT: Homodimer or homomultimer (By similarity). Component of the
CC circadian core oscillator, which includes the CRY proteins, CLOCK or
CC NPAS2, ARTNL/BMAL1 or ARTNL2/BMAL2, CSKN1D and/or CSNK1E, TIMELESS, and
CC the PER proteins (PubMed:9856465). Interacts directly with PER2; the
CC interaction with PER2 is via its second PAS domain (By similarity).
CC Interacts directly with PER1 and PER3 (By similarity). Interacts with
CC CRY2, CHEK1, ATR and ATRIP (PubMed:15798197). Interacts with CRY1 (By
CC similarity). Interacts with CLSPN (PubMed:17141802). Interacts with
CC TIPIN (PubMed:17102137, PubMed:17116885, PubMed:17296725). Interacts
CC with DDX11; this interaction increases recruitment of both proteins
CC onto chromatin in response to replication stress induction by
CC hydroxyurea (PubMed:20124417, PubMed:26503245). Interacts with PARP1;
CC interaction is direct and independent of poly-ADP-ribose
CC (PubMed:26344098, PubMed:30356214). {ECO:0000250|UniProtKB:Q9R1X4,
CC ECO:0000269|PubMed:15798197, ECO:0000269|PubMed:17102137,
CC ECO:0000269|PubMed:17116885, ECO:0000269|PubMed:17141802,
CC ECO:0000269|PubMed:17296725, ECO:0000269|PubMed:20124417,
CC ECO:0000269|PubMed:26344098, ECO:0000269|PubMed:26503245,
CC ECO:0000269|PubMed:30356214, ECO:0000269|PubMed:9856465}.
CC -!- INTERACTION:
CC Q9UNS1; O14757: CHEK1; NbExp=2; IntAct=EBI-2212315, EBI-974488;
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:17141802}. Chromosome
CC {ECO:0000269|PubMed:26344098}. Note=In response to double-strand breaks
CC (DSBs), accumulates at DNA damage sites via its interaction with PARP1.
CC {ECO:0000269|PubMed:26344098}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1 {ECO:0000269|PubMed:9856465, ECO:0000269|PubMed:9891984};
CC IsoId=Q9UNS1-1; Sequence=Displayed;
CC Name=2 {ECO:0000269|PubMed:9856465};
CC IsoId=Q9UNS1-2; Sequence=VSP_051693;
CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including brain,
CC heart, lung, liver, skeletal muscle, kidney, placenta, pancreas,
CC spleen, thymus and testis. Highest levels of expression in placenta,
CC pancreas, thymus and testis. {ECO:0000269|PubMed:9856465,
CC ECO:0000269|PubMed:9891984}.
CC -!- INDUCTION: Regulated by the cell cycle. High levels in S, G(2) and M
CC phases, with highest level in S phase. Low expression in G(0) and G(1)
CC phases. {ECO:0000269|PubMed:15798197}.
CC -!- SIMILARITY: Belongs to the timeless family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAH39842.1; Type=Miscellaneous discrepancy; Note=Contaminating sequence. Potential poly-A sequence.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/timeless/";
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DR EMBL; AB015597; BAA36499.1; -; mRNA.
DR EMBL; AF098162; AAC80011.1; -; mRNA.
DR EMBL; EU627094; ACD11488.1; -; Genomic_DNA.
DR EMBL; AC024884; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC039842; AAH39842.1; ALT_SEQ; mRNA.
DR EMBL; BC050557; AAH50557.1; -; mRNA.
DR CCDS; CCDS81699.1; -. [Q9UNS1-2]
DR CCDS; CCDS8918.1; -. [Q9UNS1-1]
DR RefSeq; NP_001317224.1; NM_001330295.1. [Q9UNS1-2]
DR RefSeq; NP_003911.2; NM_003920.4. [Q9UNS1-1]
DR PDB; 4XHT; X-ray; 1.65 A; A/B/C/D=1000-1098.
DR PDB; 4XHU; X-ray; 2.09 A; B/D=1000-1098.
DR PDB; 4XHW; X-ray; 2.85 A; A/B/C/D=1000-1098.
DR PDB; 5MQI; X-ray; 1.85 A; A=1-238, A=331-463.
DR PDB; 6T9Q; X-ray; 1.15 A; A=883-947.
DR PDB; 6TAZ; NMR; -; B=816-954.
DR PDB; 7PFO; EM; 3.20 A; K=1-1208.
DR PDB; 7PLO; EM; 2.80 A; K=1-1208.
DR PDBsum; 4XHT; -.
DR PDBsum; 4XHU; -.
DR PDBsum; 4XHW; -.
DR PDBsum; 5MQI; -.
DR PDBsum; 6T9Q; -.
DR PDBsum; 6TAZ; -.
DR PDBsum; 7PFO; -.
DR PDBsum; 7PLO; -.
DR AlphaFoldDB; Q9UNS1; -.
DR SMR; Q9UNS1; -.
DR BioGRID; 114428; 118.
DR DIP; DIP-47395N; -.
DR IntAct; Q9UNS1; 29.
DR MINT; Q9UNS1; -.
DR STRING; 9606.ENSP00000450607; -.
DR iPTMnet; Q9UNS1; -.
DR PhosphoSitePlus; Q9UNS1; -.
DR BioMuta; TIMELESS; -.
DR DMDM; 296452931; -.
DR EPD; Q9UNS1; -.
DR jPOST; Q9UNS1; -.
DR MassIVE; Q9UNS1; -.
DR MaxQB; Q9UNS1; -.
DR PaxDb; Q9UNS1; -.
DR PeptideAtlas; Q9UNS1; -.
DR PRIDE; Q9UNS1; -.
DR ProteomicsDB; 85326; -. [Q9UNS1-1]
DR ProteomicsDB; 85327; -. [Q9UNS1-2]
DR Antibodypedia; 15850; 213 antibodies from 31 providers.
DR DNASU; 8914; -.
DR Ensembl; ENST00000229201.4; ENSP00000229201.4; ENSG00000111602.12. [Q9UNS1-2]
DR Ensembl; ENST00000553532.6; ENSP00000450607.1; ENSG00000111602.12. [Q9UNS1-1]
DR GeneID; 8914; -.
DR KEGG; hsa:8914; -.
DR MANE-Select; ENST00000553532.6; ENSP00000450607.1; NM_003920.5; NP_003911.2.
DR UCSC; uc001slf.3; human. [Q9UNS1-1]
DR CTD; 8914; -.
DR DisGeNET; 8914; -.
DR GeneCards; TIMELESS; -.
DR HGNC; HGNC:11813; TIMELESS.
DR HPA; ENSG00000111602; Low tissue specificity.
DR MIM; 603887; gene.
DR neXtProt; NX_Q9UNS1; -.
DR OpenTargets; ENSG00000111602; -.
DR PharmGKB; PA36520; -.
DR VEuPathDB; HostDB:ENSG00000111602; -.
DR eggNOG; KOG1974; Eukaryota.
DR GeneTree; ENSGT00390000015124; -.
DR HOGENOM; CLU_003493_0_0_1; -.
DR InParanoid; Q9UNS1; -.
DR OMA; QGPEECG; -.
DR OrthoDB; 839367at2759; -.
DR PhylomeDB; Q9UNS1; -.
DR TreeFam; TF312802; -.
DR PathwayCommons; Q9UNS1; -.
DR Reactome; R-HSA-5693607; Processing of DNA double-strand break ends.
DR SignaLink; Q9UNS1; -.
DR SIGNOR; Q9UNS1; -.
DR BioGRID-ORCS; 8914; 723 hits in 1064 CRISPR screens.
DR ChiTaRS; TIMELESS; human.
DR GenomeRNAi; 8914; -.
DR Pharos; Q9UNS1; Tbio.
DR PRO; PR:Q9UNS1; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q9UNS1; protein.
DR Bgee; ENSG00000111602; Expressed in ventricular zone and 135 other tissues.
DR Genevisible; Q9UNS1; HS.
DR GO; GO:0000785; C:chromatin; IDA:HGNC-UCL.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IDA:HGNC-UCL.
DR GO; GO:0031298; C:replication fork protection complex; IBA:GO_Central.
DR GO; GO:0035861; C:site of double-strand break; IDA:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; IEA:Ensembl.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; IEA:Ensembl.
DR GO; GO:0044770; P:cell cycle phase transition; IMP:BHF-UCL.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:1904976; P:cellular response to bleomycin; IMP:UniProtKB.
DR GO; GO:0072719; P:cellular response to cisplatin; IMP:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IMP:UniProtKB.
DR GO; GO:0072711; P:cellular response to hydroxyurea; IMP:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
DR GO; GO:0009582; P:detection of abiotic stimulus; TAS:ProtInc.
DR GO; GO:0006281; P:DNA repair; IBA:GO_Central.
DR GO; GO:0000076; P:DNA replication checkpoint signaling; IBA:GO_Central.
DR GO; GO:0030324; P:lung development; IEA:Ensembl.
DR GO; GO:0002009; P:morphogenesis of an epithelium; ISS:UniProtKB.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; IDA:UniProtKB.
DR GO; GO:2000781; P:positive regulation of double-strand break repair; IMP:UniProtKB.
DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; IDA:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; IMP:UniProtKB.
DR GO; GO:0043111; P:replication fork arrest; IBA:GO_Central.
DR GO; GO:0048478; P:replication fork protection; IBA:GO_Central.
DR InterPro; IPR044998; Timeless.
DR InterPro; IPR007725; TIMELESS_C.
DR InterPro; IPR006906; Timeless_N.
DR PANTHER; PTHR22940; PTHR22940; 1.
DR Pfam; PF04821; TIMELESS; 1.
DR Pfam; PF05029; TIMELESS_C; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Biological rhythms; Cell cycle;
KW Cell division; Chromosome; Developmental protein; DNA damage; DNA repair;
KW Mitosis; Nucleus; Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..1208
FT /note="Protein timeless homolog"
FT /id="PRO_0000072538"
FT REGION 1..309
FT /note="Required for homodimerization and for interaction
FT with CRY1 and CHEK1"
FT /evidence="ECO:0000250|UniProtKB:Q9R1X4"
FT REGION 655..679
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 971..994
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1000..1098
FT /note="Interaction with PARP1"
FT /evidence="ECO:0000269|PubMed:26344098"
FT REGION 1082..1208
FT /note="Required for nuclear localization"
FT /evidence="ECO:0000250|UniProtKB:Q9R1X4"
FT REGION 1091..1131
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1143..1208
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 664..679
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 971..991
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1092..1106
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1117..1131
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1145..1173
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 281
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1074
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1087
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1089
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT MOD_RES 1149
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT MOD_RES 1173
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:16964243,
FT ECO:0007744|PubMed:17081983, ECO:0007744|PubMed:19690332,
FT ECO:0007744|PubMed:20068231, ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT VAR_SEQ 177
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:9856465"
FT /id="VSP_051693"
FT VARIANT 129
FT /note="A -> S (in dbSNP:rs72478986)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047879"
FT VARIANT 429
FT /note="A -> D (in a breast cancer sample; somatic
FT mutation)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036435"
FT VARIANT 455
FT /note="I -> L (in dbSNP:rs774027)"
FT /evidence="ECO:0000269|PubMed:9856465,
FT ECO:0000269|PubMed:9891984, ECO:0000269|Ref.3"
FT /id="VAR_021483"
FT VARIANT 471
FT /note="N -> S (in dbSNP:rs72478993)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047880"
FT VARIANT 831
FT /note="R -> Q (in dbSNP:rs774047)"
FT /evidence="ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:9856465, ECO:0000269|Ref.3"
FT /id="VAR_021484"
FT VARIANT 870
FT /note="M -> V (in dbSNP:rs61733875)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047881"
FT VARIANT 922
FT /note="R -> H (in dbSNP:rs72478999)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047882"
FT VARIANT 924
FT /note="R -> W (in dbSNP:rs72479000)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047883"
FT VARIANT 1008
FT /note="Q -> E (in a breast cancer sample; somatic mutation;
FT dbSNP:rs151188513)"
FT /evidence="ECO:0000269|PubMed:16959974"
FT /id="VAR_036436"
FT VARIANT 1017
FT /note="I -> T (in dbSNP:rs61376834)"
FT /evidence="ECO:0000269|Ref.3"
FT /id="VAR_047884"
FT VARIANT 1018
FT /note="P -> L (in dbSNP:rs2291739)"
FT /evidence="ECO:0000269|PubMed:15489334, ECO:0000269|Ref.3"
FT /id="VAR_021485"
FT MUTAGEN 1081
FT /note="R->G: Abolishes interaction with PARP1."
FT /evidence="ECO:0000269|PubMed:26344098"
FT HELIX 8..15
FT /evidence="ECO:0007829|PDB:5MQI"
FT STRAND 17..21
FT /evidence="ECO:0007829|PDB:5MQI"
FT STRAND 24..27
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 31..43
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 50..58
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 60..63
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 65..71
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 76..89
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 93..97
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 106..123
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 127..142
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 145..147
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 150..168
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 184..195
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 198..207
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 209..214
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 215..225
FT /evidence="ECO:0007829|PDB:5MQI"
FT TURN 226..228
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 231..234
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 336..352
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 354..367
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 369..371
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 376..391
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 396..402
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 405..424
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 426..428
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 429..451
FT /evidence="ECO:0007829|PDB:5MQI"
FT HELIX 824..837
FT /evidence="ECO:0007829|PDB:6TAZ"
FT STRAND 838..843
FT /evidence="ECO:0007829|PDB:6TAZ"
FT HELIX 845..852
FT /evidence="ECO:0007829|PDB:6TAZ"
FT HELIX 860..869
FT /evidence="ECO:0007829|PDB:6TAZ"
FT HELIX 876..880
FT /evidence="ECO:0007829|PDB:6TAZ"
FT HELIX 891..904
FT /evidence="ECO:0007829|PDB:6T9Q"
FT HELIX 910..916
FT /evidence="ECO:0007829|PDB:6T9Q"
FT HELIX 924..933
FT /evidence="ECO:0007829|PDB:6T9Q"
FT STRAND 936..939
FT /evidence="ECO:0007829|PDB:6T9Q"
FT HELIX 940..943
FT /evidence="ECO:0007829|PDB:6T9Q"
FT HELIX 1008..1012
FT /evidence="ECO:0007829|PDB:4XHT"
FT HELIX 1016..1033
FT /evidence="ECO:0007829|PDB:4XHT"
FT STRAND 1042..1044
FT /evidence="ECO:0007829|PDB:4XHW"
FT HELIX 1049..1055
FT /evidence="ECO:0007829|PDB:4XHT"
FT HELIX 1058..1067
FT /evidence="ECO:0007829|PDB:4XHT"
FT TURN 1074..1076
FT /evidence="ECO:0007829|PDB:4XHT"
FT STRAND 1078..1082
FT /evidence="ECO:0007829|PDB:4XHW"
FT HELIX 1088..1096
FT /evidence="ECO:0007829|PDB:4XHT"
SQ SEQUENCE 1208 AA; 138658 MW; 16C6C07DDC6D2701 CRC64;
MDLHMMNCEL LATCSALGYL EGDTYHKEPD CLESVKDLIR YLRHEDETRD VRQQLGAAQI
LQSDLLPILT QHHQDKPLFD AVIRLMVNLT QPALLCFGNL PKEPSFRHHF LQVLTYLQAY
KEAFASEKAF GVLSETLYEL LQLGWEERQE EDNLLIERIL LLVRNILHVP ADLDQEKKID
DDASAHDQLL WAIHLSGLDD LLLFLASSSA EEQWSLHVLE IVSLMFRDQN PEQLAGVGQG
RLAQERSADF AELEVLRQRE MAEKKTRALQ RGNRHSRFGG SYIVQGLKSI GERDLIFHKG
LHNLRNYSSD LGKQPKKVPK RRQAARELSI QRRSALNVRL FLRDFCSEFL ENCYNRLMGS
VKDHLLREKA QQHDETYYMW ALAFFMAFNR AASFRPGLVS ETLSVRTFHF IEQNLTNYYE
MMLTDRKEAA SWARRMHLAL KAYQELLATV NEMDISPDEA VRESSRIIKN NIFYVMEYRE
LFLALFRKFD ERCQPRSFLR DLVETTHLFL KMLERFCRSR GNLVVQNKQK KRRKKKKKVL
DQAIVSGNVP SSPEEVEAVW PALAEQLQCC AQNSELSMDS VVPFDAASEV PVEEQRAEAM
VRIQDCLLAG QAPQALTLLR SAREVWPEGD VFGSQDISPE EEIQLLKQIL SAPLPRQQGP
EERGAEEEEE EEEEEEEELQ VVQVSEKEFN FLDYLKRFAC STVVRAYVLL LRSYQQNSAH
TNHCIVKMLH RLAHDLKMEA LLFQLSVFCL FNRLLSDPAA GAYKELVTFA KYILGKFFAL
AAVNQKAFVE LLFWKNTAVV REMTEGYGSL DDRSSSRRAP TWSPEEEAHL RELYLANKDV
EGQDVVEAIL AHLNTVPRTR KQIIHHLVQM GLADSVKDFQ RKGTHIVLWT GDQELELQRL
FEEFRDSDDV LGHIMKNITA KRSRARIVDK LLALGLVAER RELYKKRQKK LASSILPNGA
ESLKDFCQED LEEEENLPEE DSEEEEEGGS EAEQVQGSLV LSNENLGQSL HQEGFSIPLL
WLQNCLIRAA DDREEDGCSQ AVPLVPLTEE NEEAMENEQF QQLLRKLGVR PPASGQETFW
RIPAKLSPTQ LRRAAASLSQ PEEEQKLQPE LQPKVPGEQG SDEEHCKEHR AQALRALLLA
HKKKAGLASP EEEDAVGKEP LKAAPKKRQL LDSDEEQEED EGRNRAPELG APGIQKKKRY
QIEDDEDD
