CHK1_RAT
ID CHK1_RAT Reviewed; 476 AA.
AC Q91ZN7; Q91ZN6;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2001, sequence version 1.
DT 03-AUG-2022, entry version 155.
DE RecName: Full=Serine/threonine-protein kinase Chk1;
DE EC=2.7.11.1 {ECO:0000250|UniProtKB:O14757};
DE AltName: Full=CHK1 checkpoint homolog;
DE AltName: Full=Checkpoint kinase-1;
GN Name=Chek1; Synonyms=Chk1;
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]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2), ALTERNATIVE PROMOTER USAGE,
RP AND TISSUE SPECIFICITY.
RC TISSUE=Liver;
RX PubMed=11687578; DOI=10.1074/jbc.m108253200;
RA Shann Y.-J., Hsu M.-T.;
RT "Cloning and characterization of liver-specific isoform of Chk1 gene from
RT rat.";
RL J. Biol. Chem. 276:48863-48870(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC STRAIN=Fischer 344;
RA Wang X., Wang Y.;
RT "The rat homolog of checkpoint kinase chk1.";
RL Submitted (NOV-2001) to the EMBL/GenBank/DDBJ databases.
CC -!- FUNCTION: Serine/threonine-protein kinase which is required for
CC checkpoint-mediated cell cycle arrest and activation of DNA repair in
CC response to the presence of DNA damage or unreplicated DNA. May also
CC negatively regulate cell cycle progression during unperturbed cell
CC cycles. This regulation is achieved by a number of mechanisms that
CC together help to preserve the integrity of the genome. Recognizes the
CC substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates
CC CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and
CC 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding
CC sites for 14-3-3 proteins which inhibit CDC25A and CDC25C.
CC Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279'
CC and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A
CC at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-
CC 79', 'Ser-82' and 'Ser-88' by NEK11, which is required for
CC polyubiquitination and degradation of CDCD25A. Inhibition of CDC25
CC leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin
CC complexes and blocks cell cycle progression. Also phosphorylates NEK6.
CC Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the
CC release of RAD51 from BRCA2 and enhances the association of RAD51 with
CC chromatin, thereby promoting DNA repair by homologous recombination.
CC Phosphorylates multiple sites within the C-terminus of TP53, which
CC promotes activation of TP53 by acetylation and promotes cell cycle
CC arrest and suppression of cellular proliferation. Also promotes repair
CC of DNA cross-links through phosphorylation of FANCE. Binds to and
CC phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent
CC phosphorylation of the chromatin assembly factor ASF1A. This may
CC enhance chromatin assembly both in the presence or absence of DNA
CC damage. May also play a role in replication fork maintenance through
CC regulation of PCNA (By similarity). May regulate the transcription of
CC genes that regulate cell-cycle progression through the phosphorylation
CC of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads
CC to epigenetic inhibition of a subset of genes (By similarity). May also
CC phosphorylate RB1 to promote its interaction with the E2F family of
CC transcription factors and subsequent cell cycle arrest. Phosphorylates
CC SPRTN, promoting SPRTN recruitment to chromatin (By similarity).
CC Reduces replication stress and activates the G2/M checkpoint, by
CC phosphorylating and inactivating PABIR1/FAM122A and promoting the
CC serine/threonine-protein phosphatase 2A-mediated dephosphorylation and
CC stabilization of WEE1 levels and activity (By similarity).
CC {ECO:0000250|UniProtKB:O14757, ECO:0000250|UniProtKB:O35280}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-seryl-[protein] = ADP + H(+) + O-phospho-L-seryl-
CC [protein]; Xref=Rhea:RHEA:17989, Rhea:RHEA-COMP:9863, Rhea:RHEA-
CC COMP:11604, ChEBI:CHEBI:15378, ChEBI:CHEBI:29999, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:83421, ChEBI:CHEBI:456216; EC=2.7.11.1;
CC Evidence={ECO:0000250|UniProtKB:O14757};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + L-threonyl-[protein] = ADP + H(+) + O-phospho-L-
CC threonyl-[protein]; Xref=Rhea:RHEA:46608, Rhea:RHEA-COMP:11060,
CC Rhea:RHEA-COMP:11605, ChEBI:CHEBI:15378, ChEBI:CHEBI:30013,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61977, ChEBI:CHEBI:456216;
CC EC=2.7.11.1; Evidence={ECO:0000250|UniProtKB:O14757};
CC -!- ACTIVITY REGULATION: Activated through phosphorylation predominantly by
CC ATR but also by ATM in response to DNA damage or inhibition of DNA
CC replication. Activation is modulated by several mediators including
CC CLSPN, BRCA1 and FEM1B. Proteolytic cleavage at the C-terminus by SPRTN
CC during normal DNA replication activates the protein kinase activity.
CC {ECO:0000250|UniProtKB:O14757}.
CC -!- SUBUNIT: Interacts (phosphorylated by ATR) with RAD51. Interacts with
CC and phosphorylates CLSPN, an adapter protein that regulates the ATR-
CC dependent phosphorylation of CHEK1. Interacts with BRCA1. Interacts
CC with and phosphorylates CDC25A, CDC25B and CDC25C. Interacts with
CC FBXO6, which regulates CHEK1. Interacts with PPM1D, which regulates
CC CHEK1 through dephosphorylation. Interacts with TIMELESS; DNA damage-
CC dependent. Interacts with FEM1B; activates CHEK1 in response to stress.
CC Interacts with TLK1. Interacts with XPO1 and YWHAZ. Interacts with
CC CDK5RAP3; antagonizes CHEK1. {ECO:0000250|UniProtKB:O14757}.
CC -!- SUBCELLULAR LOCATION: Nucleus {ECO:0000250|UniProtKB:O14757}.
CC Chromosome {ECO:0000250|UniProtKB:O14757}. Cytoplasm
CC {ECO:0000250|UniProtKB:O14757}. Cytoplasm, cytoskeleton, microtubule
CC organizing center, centrosome {ECO:0000250|UniProtKB:O14757}.
CC Note=Nuclear export is mediated at least in part by XPO1/CRM1. Also
CC localizes to the centrosome specifically during interphase, where it
CC may protect centrosomal CDC2 kinase from inappropriate activation by
CC cytoplasmic CDC25B. Proteolytic cleavage at the C-terminus by SPRTN
CC promotes removal from chromatin. {ECO:0000250|UniProtKB:O14757}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative promoter usage; Named isoforms=2;
CC Name=1;
CC IsoId=Q91ZN7-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q91ZN7-2; Sequence=VSP_015770;
CC -!- TISSUE SPECIFICITY: [Isoform 1]: Expressed in brain, heart, liver,
CC lung, skeletal muscle, spleen and testis.
CC {ECO:0000269|PubMed:11687578}.
CC -!- TISSUE SPECIFICITY: [Isoform 2]: Expressed only in liver.
CC {ECO:0000269|PubMed:11687578}.
CC -!- DOMAIN: The autoinhibitory region (AIR) inhibits the activity of the
CC kinase domain. {ECO:0000250|UniProtKB:O14757}.
CC -!- PTM: Phosphorylated by ATR in a RAD17-dependent manner in response to
CC ultraviolet irradiation and inhibition of DNA replication.
CC Phosphorylated by ATM in response to ionizing irradiation. ATM and ATR
CC can both phosphorylate Ser-317 and Ser-345 and this results in enhanced
CC kinase activity. Phosphorylation at Ser-345 induces a change in the
CC conformation of the protein, activates the kinase activity and is a
CC prerequisite for interaction with FBXO6 and subsequent ubiquitination
CC at Lys-436. Phosphorylation at Ser-345 also increases binding to 14-3-3
CC proteins and promotes nuclear retention. Conversely, dephosphorylation
CC at Ser-345 by PPM1D may contribute to exit from checkpoint mediated
CC cell cycle arrest. Phosphorylation at Ser-280 by AKT1/PKB, may promote
CC mono and/or diubiquitination. Also phosphorylated at undefined residues
CC during mitotic arrest, resulting in decreased activity (By similarity).
CC {ECO:0000250|UniProtKB:O14757}.
CC -!- PTM: Ubiquitinated. Mono or diubiquitination promotes nuclear
CC exclusion. The activated form (phosphorylated on Ser-345) is
CC polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase
CC complex containing FBXO6 promoting its degradation. Ubiquitination and
CC degradation are required to terminate the checkpoint and ensure that
CC activated CHEK1 does not accumulate as cells progress through S phase,
CC when replication forks encounter transient impediments during normal
CC DNA replication. 'Lys-63'-mediated ubiquitination by TRAF4 at Lys-132
CC activates cell cycle arrest and activation of DNA repair (By
CC similarity). {ECO:0000250|UniProtKB:O14757}.
CC -!- PTM: Proteolytically cleaved at the C-terminus by SPRTN during normal
CC DNA replication, thereby promoting CHEK1 removal from chromatin and
CC activating the protein kinase activity. {ECO:0000250|UniProtKB:O14757}.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr
CC protein kinase family. NIM1 subfamily. {ECO:0000305}.
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DR EMBL; AF414135; AAK98619.1; -; mRNA.
DR EMBL; AF414136; AAK98620.1; -; mRNA.
DR EMBL; AF443592; AAL37894.1; -; mRNA.
DR RefSeq; NP_536325.1; NM_080400.1. [Q91ZN7-1]
DR RefSeq; XP_008764264.1; XM_008766042.2. [Q91ZN7-1]
DR RefSeq; XP_008764265.1; XM_008766043.1. [Q91ZN7-1]
DR AlphaFoldDB; Q91ZN7; -.
DR SMR; Q91ZN7; -.
DR BioGRID; 250797; 2.
DR STRING; 10116.ENSRNOP00000011226; -.
DR PhosphoSitePlus; Q91ZN7; -.
DR PaxDb; Q91ZN7; -.
DR PRIDE; Q91ZN7; -.
DR Ensembl; ENSRNOT00000011226; ENSRNOP00000011226; ENSRNOG00000071217. [Q91ZN7-1]
DR GeneID; 140583; -.
DR KEGG; rno:140583; -.
DR UCSC; RGD:620545; rat. [Q91ZN7-1]
DR CTD; 1111; -.
DR RGD; 620545; Chek1.
DR eggNOG; KOG0590; Eukaryota.
DR GeneTree; ENSGT00940000159682; -.
DR HOGENOM; CLU_000288_59_8_1; -.
DR InParanoid; Q91ZN7; -.
DR OrthoDB; 698464at2759; -.
DR PhylomeDB; Q91ZN7; -.
DR TreeFam; TF351441; -.
DR Reactome; R-RNO-1433557; Signaling by SCF-KIT.
DR Reactome; R-RNO-176187; Activation of ATR in response to replication stress.
DR Reactome; R-RNO-5693607; Processing of DNA double-strand break ends.
DR Reactome; R-RNO-5693616; Presynaptic phase of homologous DNA pairing and strand exchange.
DR Reactome; R-RNO-6804756; Regulation of TP53 Activity through Phosphorylation.
DR Reactome; R-RNO-69473; G2/M DNA damage checkpoint.
DR Reactome; R-RNO-69601; Ubiquitin Mediated Degradation of Phosphorylated Cdc25A.
DR Reactome; R-RNO-8953750; Transcriptional Regulation by E2F6.
DR SABIO-RK; Q91ZN7; -.
DR PRO; PR:Q91ZN7; -.
DR Proteomes; UP000002494; Chromosome 8.
DR Bgee; ENSRNOG00000031896; Expressed in jejunum and 18 other tissues.
DR ExpressionAtlas; Q91ZN7; baseline and differential.
DR Genevisible; Q91ZN7; RN.
DR GO; GO:0005813; C:centrosome; ISS:UniProtKB.
DR GO; GO:0000785; C:chromatin; ISS:UniProtKB.
DR GO; GO:0000781; C:chromosome, telomeric region; IEA:Ensembl.
DR GO; GO:0000794; C:condensed nuclear chromosome; ISS:UniProtKB.
DR GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR GO; GO:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0005634; C:nucleus; ISS:UniProtKB.
DR GO; GO:0032991; C:protein-containing complex; ISO:RGD.
DR GO; GO:0005657; C:replication fork; ISO:RGD.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0035402; F:histone kinase activity (H3-T11 specific); ISS:UniProtKB.
DR GO; GO:0019904; F:protein domain specific binding; ISO:RGD.
DR GO; GO:0004672; F:protein kinase activity; IDA:RGD.
DR GO; GO:0106310; F:protein serine kinase activity; IEA:RHEA.
DR GO; GO:0004674; F:protein serine/threonine kinase activity; ISS:UniProtKB.
DR GO; GO:0006915; P:apoptotic process; ISO:RGD.
DR GO; GO:1902742; P:apoptotic process involved in development; ISO:RGD.
DR GO; GO:0071313; P:cellular response to caffeine; IEP:RGD.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; ISS:UniProtKB.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; ISO:RGD.
DR GO; GO:0071310; P:cellular response to organic substance; IEP:RGD.
DR GO; GO:0000077; P:DNA damage checkpoint signaling; ISS:UniProtKB.
DR GO; GO:0006975; P:DNA damage induced protein phosphorylation; IMP:RGD.
DR GO; GO:0006281; P:DNA repair; ISO:RGD.
DR GO; GO:0045815; P:epigenetic maintenance of chromatin in transcription-competent conformation; ISS:UniProtKB.
DR GO; GO:0000086; P:G2/M transition of mitotic cell cycle; ISO:RGD.
DR GO; GO:0001833; P:inner cell mass cell proliferation; ISO:RGD.
DR GO; GO:0035556; P:intracellular signal transduction; IBA:GO_Central.
DR GO; GO:0007095; P:mitotic G2 DNA damage checkpoint signaling; ISO:RGD.
DR GO; GO:0044818; P:mitotic G2/M transition checkpoint; ISS:UniProtKB.
DR GO; GO:2000279; P:negative regulation of DNA biosynthetic process; IMP:RGD.
DR GO; GO:0010972; P:negative regulation of G2/M transition of mitotic cell cycle; IMP:RGD.
DR GO; GO:0045839; P:negative regulation of mitotic nuclear division; ISS:UniProtKB.
DR GO; GO:0006997; P:nucleus organization; ISO:RGD.
DR GO; GO:0018107; P:peptidyl-threonine phosphorylation; ISS:UniProtKB.
DR GO; GO:0045787; P:positive regulation of cell cycle; ISO:RGD.
DR GO; GO:0006468; P:protein phosphorylation; IDA:RGD.
DR GO; GO:0042127; P:regulation of cell population proliferation; ISO:RGD.
DR GO; GO:0010569; P:regulation of double-strand break repair via homologous recombination; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; ISO:RGD.
DR GO; GO:2000615; P:regulation of histone H3-K9 acetylation; ISS:UniProtKB.
DR GO; GO:0046602; P:regulation of mitotic centrosome separation; ISS:UniProtKB.
DR GO; GO:0010767; P:regulation of transcription from RNA polymerase II promoter in response to UV-induced DNA damage; ISS:UniProtKB.
DR CDD; cd14069; STKc_Chk1; 1.
DR InterPro; IPR034670; Chk1_catalytic_dom.
DR InterPro; IPR011009; Kinase-like_dom_sf.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR008271; Ser/Thr_kinase_AS.
DR Pfam; PF00069; Pkinase; 1.
DR SMART; SM00220; S_TKc; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00108; PROTEIN_KINASE_ST; 1.
PE 2: Evidence at transcript level;
KW Alternative promoter usage; ATP-binding; Cell cycle; Chromosome; Cytoplasm;
KW Cytoskeleton; DNA damage; DNA repair; Isopeptide bond; Kinase;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Reference proteome;
KW Serine/threonine-protein kinase; Transferase; Ubl conjugation.
FT CHAIN 1..476
FT /note="Serine/threonine-protein kinase Chk1"
FT /id="PRO_0000085850"
FT DOMAIN 9..265
FT /note="Protein kinase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT REGION 1..265
FT /note="Interaction with CLSPN"
FT /evidence="ECO:0000250"
FT REGION 267..329
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 391..476
FT /note="Autoinhibitory region"
FT /evidence="ECO:0000250"
FT COMPBIAS 280..329
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 130
FT /note="Proton acceptor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159,
FT ECO:0000255|PROSITE-ProRule:PRU10027"
FT BINDING 15..23
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT BINDING 38
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00159"
FT MOD_RES 280
FT /note="Phosphoserine; by PKB/AKT1"
FT /evidence="ECO:0000250|UniProtKB:O35280"
FT MOD_RES 286
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 296
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 301
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 317
FT /note="Phosphoserine; by ATM and ATR"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 345
FT /note="Phosphoserine; by ATM and ATR"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 463
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O35280"
FT MOD_RES 467
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT MOD_RES 468
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT CROSSLNK 132
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT CROSSLNK 436
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:O14757"
FT VAR_SEQ 1..282
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:11687578"
FT /id="VSP_015770"
SQ SEQUENCE 476 AA; 54428 MW; 5635614A3E5B4657 CRC64;
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRI TEEAVAVKIV DMKRAIDCPE NIKKEICINK
MLNHENVVKF YGHRREGNIQ YLFLEYCSGG ELFDRIEPDI GMPEQDAQRF FHQLMAGVVY
LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRHNNR ERLLNKMCGT LPYVAPELLK
RKEFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA
LLHKILVENP SARITIPDIK KDRWYNKPLN RGAKRPRATS GGMSESSSGF SKHIHSNLDF
SPINSGSSEE NVKFSSSQPE PRTGLSLWDT GPSNVDKLVQ GISFSQPTCP DHMLVNSQLL
GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETFEKL GYQWKKSCMN QVTVSTMDRR
NNKLIFKINL VEMDEKILVD FRLSKGDGLE FKRHFLKIKG KLSDIVSSQK VWFPVT
