TIM_RAT
ID TIM_RAT Reviewed; 1205 AA.
AC Q9Z2Y1;
DT 15-MAR-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1999, sequence version 1.
DT 03-AUG-2022, entry version 113.
DE RecName: Full=Protein timeless homolog;
DE Short=rTIM;
DE AltName: Full=Timeless-like protein;
DE Short=rTLP;
GN Name=Timeless {ECO:0000312|RGD:620939};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1] {ECO:0000305, ECO:0000312|EMBL:BAA34400.1}
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, SUBCELLULAR LOCATION, AND
RP INTERACTION WITH PER2.
RC STRAIN=Wistar {ECO:0000312|EMBL:BAA34400.1};
RC TISSUE=Hypothalamus {ECO:0000269|PubMed:11112428};
RX PubMed=11112428; DOI=10.1006/bbrc.2000.3927;
RA Sakamoto S., Miyazaki K., Fukui H., Oishi K., Hayasaka N., Okada M.,
RA Kamakura M., Taniguchi T., Nagai K., Ishida N.;
RT "Molecular characterization and nuclear localization of rat timeless-like
RT gene product.";
RL Biochem. Biophys. Res. Commun. 279:131-138(2000).
RN [2] {ECO:0000305}
RP FUNCTION.
RX PubMed=10963667; DOI=10.1073/pnas.97.18.10038;
RA Li Z., Stuart R.O., Qiao J., Pavlova A., Bush K.T., Pohl M., Sakurai H.,
RA Nigam S.K.;
RT "A role for Timeless in epithelial morphogenesis during kidney
RT development.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:10038-10043(2000).
RN [3] {ECO:0000305}
RP TISSUE SPECIFICITY, AND INDUCTION.
RX PubMed=15094047; DOI=10.1016/s0014-5793(04)00322-9;
RA Muehlbauer E., Wolgast S., Finckh U., Peschke D., Peschke E.;
RT "Indication of circadian oscillations in the rat pancreas.";
RL FEBS Lett. 564:91-96(2004).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-1169 AND THR-1174, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22673903; DOI=10.1038/ncomms1871;
RA Lundby A., Secher A., Lage K., Nordsborg N.B., Dmytriyev A., Lundby C.,
RA Olsen J.V.;
RT "Quantitative maps of protein phosphorylation sites across 14 different rat
RT organs and tissues.";
RL Nat. Commun. 3:876-876(2012).
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 (By similarity). 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 (By similarity). TIMELESS promotes
CC TIPIN nuclear localization (By similarity). Involved in cell survival
CC after DNA damage or replication stress by promoting DNA repair (By
CC similarity). In response to double-strand breaks (DSBs), accumulates at
CC DNA damage sites and promotes homologous recombination repair via its
CC interaction with PARP1 (By similarity). May be specifically required
CC for the ATR-CHEK1 pathway in the replication checkpoint induced by
CC hydroxyurea or ultraviolet light (By similarity). Involved in the
CC determination of period length and in the DNA damage-dependent phase
CC advancing of the circadian clock (By similarity). Negatively regulates
CC CLOCK|NPAS2-ARTNL/BMAL1|ARTNL2/BMAL2-induced transactivation of PER1
CC possibly via translocation of PER1 into the nucleus (By similarity).
CC May also play an important role in epithelial cell morphogenesis and
CC formation of branching tubules (PubMed:10963667).
CC {ECO:0000250|UniProtKB:Q9UNS1, ECO:0000269|PubMed:10963667}.
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 (By similarity). Interacts directly with PER2; the
CC interaction with PER2 is via its second PAS domain (PubMed:11112428).
CC Interacts directly with PER1 and PER3 (By similarity). Interacts with
CC CRY2, CHEK1, ATR and ATRIP (By similarity). Interacts with CRY1 (By
CC similarity). Interacts with CLSPN. Interacts with TIPIN. Interacts with
CC DDX11; this interaction increases recruitment of both proteins onto
CC chromatin in response to replication stress induction by hydroxyurea.
CC Interacts with PARP1; interaction is direct and independent of poly-
CC ADP-ribose (By similarity). {ECO:0000250|UniProtKB:Q9R1X4,
CC ECO:0000250|UniProtKB:Q9UNS1, ECO:0000269|PubMed:11112428}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000269|PubMed:11112428}. Chromosome
CC {ECO:0000250|UniProtKB:Q9UNS1}. Note=In response to double-strand
CC breaks (DSBs), accumulates at DNA damage sites via its interaction with
CC PARP1. {ECO:0000250|UniProtKB:Q9UNS1}.
CC -!- TISSUE SPECIFICITY: Expressed in all tissues examined including brain,
CC eye, lung, heart, liver, kidney, pancreas, placenta and testis. Highest
CC levels of expression in eye, lung, liver, placenta and kidney.
CC Expressed throughout the suprachiasmatic nucleus (SCN).
CC {ECO:0000269|PubMed:11112428, ECO:0000269|PubMed:15094047}.
CC -!- INDUCTION: In both brain and pancreas, no circadian oscillation was
CC detected. {ECO:0000269|PubMed:11112428, ECO:0000269|PubMed:15094047}.
CC -!- SIMILARITY: Belongs to the timeless family. {ECO:0000305}.
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DR EMBL; AB019576; BAA34400.1; -; mRNA.
DR PIR; T13959; T13959.
DR RefSeq; NP_112630.1; NM_031340.1.
DR AlphaFoldDB; Q9Z2Y1; -.
DR SMR; Q9Z2Y1; -.
DR STRING; 10116.ENSRNOP00000043366; -.
DR iPTMnet; Q9Z2Y1; -.
DR PhosphoSitePlus; Q9Z2Y1; -.
DR PaxDb; Q9Z2Y1; -.
DR PRIDE; Q9Z2Y1; -.
DR GeneID; 83508; -.
DR KEGG; rno:83508; -.
DR UCSC; RGD:620939; rat.
DR CTD; 8914; -.
DR RGD; 620939; Timeless.
DR eggNOG; KOG1974; Eukaryota.
DR InParanoid; Q9Z2Y1; -.
DR OrthoDB; 839367at2759; -.
DR PhylomeDB; Q9Z2Y1; -.
DR Reactome; R-RNO-5693607; Processing of DNA double-strand break ends.
DR PRO; PR:Q9Z2Y1; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0000785; C:chromatin; ISO:RGD.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0031298; C:replication fork protection complex; IBA:GO_Central.
DR GO; GO:0035861; C:site of double-strand break; ISS:UniProtKB.
DR GO; GO:0003677; F:DNA binding; IBA:GO_Central.
DR GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR GO; GO:0001658; P:branching involved in ureteric bud morphogenesis; IMP:MGI.
DR GO; GO:0048754; P:branching morphogenesis of an epithelial tube; ISO:RGD.
DR GO; GO:0044770; P:cell cycle phase transition; ISO:RGD.
DR GO; GO:0051301; P:cell division; IEA:UniProtKB-KW.
DR GO; GO:1904976; P:cellular response to bleomycin; ISS:UniProtKB.
DR GO; GO:0072719; P:cellular response to cisplatin; ISS:UniProtKB.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0072711; P:cellular response to hydroxyurea; ISS:UniProtKB.
DR GO; GO:0007623; P:circadian rhythm; ISS:UniProtKB.
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:0001822; P:kidney development; IMP:RGD.
DR GO; GO:0030324; P:lung development; ISO:RGD.
DR GO; GO:0002009; P:morphogenesis of an epithelium; IEP:UniProtKB.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD.
DR GO; GO:0045892; P:negative regulation of transcription, DNA-templated; ISS:UniProtKB.
DR GO; GO:0042753; P:positive regulation of circadian rhythm; IMP:RGD.
DR GO; GO:2000781; P:positive regulation of double-strand break repair; ISS:UniProtKB.
DR GO; GO:1905168; P:positive regulation of double-strand break repair via homologous recombination; ISS:UniProtKB.
DR GO; GO:0042752; P:regulation of circadian rhythm; ISS: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 Biological rhythms; Cell cycle; Cell division; Chromosome;
KW Developmental protein; DNA damage; DNA repair; Mitosis; Nucleus;
KW Phosphoprotein; Reference proteome; Transcription;
KW Transcription regulation.
FT CHAIN 1..1205
FT /note="Protein timeless homolog"
FT /id="PRO_0000072540"
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 651..676
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 942..997
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 999..1097
FT /note="Interaction with PARP1"
FT /evidence="ECO:0000250|UniProtKB:Q9UNS1"
FT REGION 1081..1205
FT /note="Required for nuclear localization"
FT /evidence="ECO:0000250|UniProtKB:Q9R1X4"
FT REGION 1092..1205
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 658..676
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 963..988
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1096..1113
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1142..1169
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 281
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UNS1"
FT MOD_RES 1073
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UNS1"
FT MOD_RES 1086
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9UNS1"
FT MOD_RES 1088
FT /note="Phosphothreonine"
FT /evidence="ECO:0000250|UniProtKB:Q9UNS1"
FT MOD_RES 1169
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:22673903"
FT MOD_RES 1174
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:22673903"
SQ SEQUENCE 1205 AA; 138565 MW; C118B6ACF1DDA03D CRC64;
MDLYMMNCEL LATCSALGYL EGGTYHKEPD CLESVKDLIR YLRHEDETRD VRQQLGAAQI
LQSDLLPILT QHRQDKPLFD AVIRLMVNLT QPALLCFGSV PKDPTVRHHF LQVLTYLQAY
KEAFASEKAF GVLSETLYEL LQLGWEDRQE EDNLLIERIL LLVRNILHVP ANLEQEKRID
DDASIHDRLL WAIHLSGMDD LLLFLSSSSA EQQWSLHVLE IISLMFRDQK PEQLAGVGQG
RLAQERSTDL AELEVLRQRE VAEKRARALQ RGNRHSRFGG SYVVQGLKSI GERDVVFHKG
LHNLQNYSSD LGKQPRRVPK RRQAAQELSV HRRSVLNVRL FLRDFCSEFL ENCYNPLMGA
VKDHLLREKA QQHDETYYMW AMAFFMAFNR AAAFRPGFVS ETLSIRTFHF VEQNLTNYYE
MMLTDRKEAA SWARRMHLAL KAYQELLATV NEMDMCPDDA VRESSRIIKN NIFYMMEYRE
LFLALFRKFD ERYHPRSFLC DLVETTHLFL KMLERFCRSR GNLMVQNKRK KRKKKKKAQE
QGVAFSRSPE ELQAMWSALA ERLLQCAQEP ELSVDSIIPF DAASEVPVEE QRVEAMVRIQ
DCLVAGQAPQ ALALLRSARE VWPEGNVFGS PVISPGEEMQ LLKQILSATL PRQQEPVEGD
AEEEDEEEEE EEEEELQVVQ VSEKEFKFLD YLKRFACSTI VRAYVLLLRS YRQNSAHTNH
CIAKMLHRLA HDLGMEALLF QLSLFCLFNQ LLSDPAAAAY KELVTFAKYI LGKFFALAAV
NQKAFVELLF WKNTSVVREM TQGYGSLDSG SCSHRAPVWS SEEEAQLQEL YLAHKDVEGQ
DVVETILAHL KAVPRTRKQV IHHLVRMGLA DSVKDFQRKG TQIVLWTEDQ ELELQRLFEE
FQDSDDVLGH IMKNITAKRS RARVVDKLLA LGLVSERRQL HKKRRKKLAP SCMQNGEESQ
RDAWQEDPEE EEEKEGLPES EGEENEEDLL AGQVQGSSSL SAENLRQSLC QDGLSAPLLW
LQSSLIRAAD DREEDGCSQA IPLVPLTEEN EEAMENKQFQ HLLRKLGIRA PCSGQETFWR
IPAKLSSTQL RRVAASLSER ENKEEREEEP EPNPGVPGEQ SPSEEHQVRA PRALLSARKR
KAGLVFPKEE ATGEEEWKSV PKKQQLLDSD EEDTDDERGG QAAVSGTLRI HKEKRFLVED
EDEDY
