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Description:
Serine/threonine-protein kinase Chk1 (EC 2.7.1.37).
Molecular weight: 54420
View which proteins in this organism that is involved with DNA Repair;
classified after biological processes (using data from the GOA project):
DNA repair( GO:0006281 )
Important dates:
30-MAY-2000, integrated into UniProtKB/Swiss-Prot.
01-JAN-1998, sequence version 1.
07-MAR-2006, entry version 62.
Phylogenetic order:
Eukaryota Metazoa Chordata Craniata Vertebrata Euteleostomi Mammalia Eutheria Euarchontoglires Primates Catarrhini Hominidae Homo.
To calculate the pI (Isoelectric point - the pH where a protein has a neutral charge),
go to this page and enter the protein ID (e.g 3MG_ECOLI): http://us.expasy.org/tools/pi_tool.html
Links to references in other databases for protein CHK1_HUMAN:
| Database | Pointer | Add. info#1 | Add. info#2 |
| EMBL | AF016582 | AAC51736.1 | - |
| EMBL | AF032874 | AAB88852.1 | - |
| EMBL | AB032387 | BAA84577.1 | - |
| EMBL | AF527555 | AAM78553.1 | - |
| EMBL | BC004202 | AAH04202.1 | - |
| EMBL | BC017575 | AAH17575.1 | - |
| PDB | 1IA8 | X-ray | A=1-289. |
| PDB | 1NVQ | X-ray | A=1-289. |
| PDB | 1NVR | X-ray | A=1-289. |
| PDB | 1NVS | X-ray | A=1-289. |
| PDB | 2BR1 | X-ray | A=1-289. |
| PDB | 2BRB | X-ray | A=1-289. |
| PDB | 2BRG | X-ray | A=1-289. |
| PDB | 2BRH | X-ray | A=1-289. |
| PDB | 2BRM | X-ray | A=1-289. |
| PDB | 2BRN | X-ray | A=1-289. |
| PDB | 2BRO | X-ray | A=1-289. |
| PDB | 2C3J | X-ray | A=1-289. |
| PDB | 2C3K | X-ray | A=1-289. |
| PDB | 2C3L | X-ray | A=1-289. |
| Ensembl | ENSG00000149554 | Homo sapiens.1 | |
| H-InvDB | HIX0020525 | -.1 | |
| HGNC | HGNC:1925 | CHEK1.1 | |
| MIM | 603078 | gene. | |
| Reactome | O14757 | -.1 | |
| GO | GO:0000794 | C:condensed nuclear chromosome | TAS. |
| GO | GO:0004672 | F:protein kinase activity | TAS. |
| GO | GO:0000077 | P:DNA damage checkpoint | TAS. |
| GO | GO:0007276 | P:gametogenesis | TAS. |
| GO | GO:0007131 | P:meiotic recombination | TAS. |
| GO | GO:0008285 | P:negative regulation of cell proliferation | TAS. |
| GO | GO:0000079 | P:regulation of cyclin dependent protein kina... | TAS. |
| InterPro | IPR000719 | Prot_kinase. | |
| InterPro | IPR008271 | Ser_thr_pkin_AS. | |
| InterPro | IPR002290 | Ser_thr_pkinase. | |
| InterPro | IPR001245 | Tyr_pkinase. | |
| Pfam | PF00069 | Pkinase | 1. |
| ProDom | PD000001 | Prot_kinase | 1. |
| SMART | SM00220 | S_TKc | 1. |
| PROSITE | PS00107 | PROTEIN_KINASE_ATP | 1. |
| PROSITE | PS50011 | PROTEIN_KINASE_DOM | 1. |
| PROSITE | PS00108 | PROTEIN_KINASE_ST | 1. |
Keywords:
3D-structure; ATP-binding; Cell cycle; DNA damage; DNA repair; Kinase; Nuclear protein; Nucleotide-binding; Phosphorylation; Polymorphism; Serine/threonine-protein kinase; Transferase; Ubl conjugation.
References:
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, INTERACTIONS WITH CDC25A; CDC25B
RP AND CDC25C, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, PHOSPHORYLATION,
RP AND MUTAGENESIS OF ASP-130.
RX MEDLINE=97426625; PubMed=9278511; DOI=10.1126/science.277.5331.1497;
RA Sanchez Y., Wong C., Thoma R.S., Richman R., Wu Z., Piwnica-Worms H.,
RA Elledge S.J.;
RT "Conservation of the Chk1 checkpoint pathway in mammals: linkage of
RT DNA damage to Cdk regulation through Cdc25.";
RL Science 277:1497-1501(1997).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX MEDLINE=98044285; PubMed=9382850; DOI=10.1016/S0960-9822(06)00417-9;
RA Flaggs G., Plug A.W., Dunks K.M., Mundt K.E., Ford J.C.,
RA Quiggle M.R.E., Taylor E.M., Westphal C.H., Ashley T., Hoekstra M.F.,
RA Carr A.M.;
RT "Atm-dependent interactions of a mammalian chk1 homolog with meiotic
RT chromosomes.";
RL Curr. Biol. 7:977-986(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX MEDLINE=20184068; PubMed=10717241;
RA Semba S., Ouyang H., Han S.-Y., Kato Y., Horii A.;
RT "Analysis of the candidate target genes for mutation in microsatellite
RT instability-positive cancers of the colorectum, stomach, and
RT endometrium.";
RL Int. J. Oncol. 16:731-737(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT GLN-156.
RA Rieder M.J., Livingston R.J., Braun A.C., Montoya M.A., Chung M.-W.,
RA Miyamoto K.E., Nguyen C.P., Nguyen D.A., Poel C.L., Robertson P.D.,
RA Schackwitz W.S., Sherwood J.K., Witrak L.A., Nickerson D.A.;
RT "NIEHS-SNPs, environmental genome project, NIEHS ES15478, Department
RT of Genome Sciences, Seattle, WA (URL: http://egp.gs.washington.edu).";
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Bone marrow, and Muscle;
RX MEDLINE=22388257; PubMed=12477932; DOI=10.1073/pnas.242603899;
RA Strausberg R.L., Feingold E.A., Grouse L.H., Derge J.G.,
RA Klausner R.D., Collins F.S., Wagner L., Shenmen C.M., Schuler G.D.,
RA Altschul S.F., Zeeberg B., Buetow K.H., Schaefer C.F., Bhat N.K.,
RA Hopkins R.F., Jordan H., Moore T., Max S.I., Wang J., Hsieh F.,
RA Diatchenko L., Marusina K., Farmer A.A., Rubin G.M., Hong L.,
RA Stapleton M., Soares M.B., Bonaldo M.F., Casavant T.L., Scheetz T.E.,
RA Brownstein M.J., Usdin T.B., Toshiyuki S., Carninci P., Prange C.,
RA Raha S.S., Loquellano N.A., Peters G.J., Abramson R.D., Mullahy S.J.,
RA Bosak S.A., McEwan P.J., McKernan K.J., Malek J.A., Gunaratne P.H.,
RA Richards S., Worley K.C., Hale S., Garcia A.M., Gay L.J., Hulyk S.W.,
RA Villalon D.K., Muzny D.M., Sodergren E.J., Lu X., Gibbs R.A.,
RA Fahey J., Helton E., Ketteman M., Madan A., Rodrigues S., Sanchez A.,
RA Whiting M., Madan A., Young A.C., Shevchenko Y., Bouffard G.G.,
RA Blakesley R.W., Touchman J.W., Green E.D., Dickson M.C.,
RA Rodriguez A.C., Grimwood J., Schmutz J., Myers R.M.,
RA Butterfield Y.S.N., Krzywinski M.I., Skalska U., Smailus D.E.,
RA Schnerch A., Schein J.E., Jones S.J.M., Marra M.A.;
RT "Generation and initial analysis of more than 15,000 full-length human
RT and mouse cDNA sequences.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:16899-16903(2002).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF ASP-130.
RA Shieh S.-Y., Ahn J., Tamai K., Taya Y., Prives C.;
RT "The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2)
RT phosphorylate p53 at multiple DNA damage-inducible sites.";
RL Genes Dev. 14:289-300(2000).
RN [7]
RP ERRATUM.
RA Shieh S.-Y., Ahn J., Tamai K., Taya Y., Prives C.;
RL Genes Dev. 14:750-750(2000).
RN [8]
RP PHOSPHORYLATION SITE SER-345.
RX MEDLINE=20317029; PubMed=10859164;
RA Liu Q., Guntuku S., Cui X.-S., Matsuoka S., Cortez D., Tamai K.,
RA Luo G., Carattini-Rivera S., DeMayo F., Bradley A., Donehower L.A.,
RA Elledge S.J.;
RT "Chk1 is an essential kinase that is regulated by Atr and required for
RT the G(2)/M DNA damage checkpoint.";
RL Genes Dev. 14:1448-1459(2000).
RN [9]
RP FUNCTION, PHOSHPORYLATION BY ATR, AND MUTAGENESIS OF ASP-130.
RX PubMed=11535615; DOI=10.1083/jcb.200104099;
RA Feijoo C., Hall-Jackson C., Wu R., Jenkins D., Leitch J.,
RA Gilbert D.M., Smythe C.;
RT "Activation of mammalian Chk1 during DNA replication arrest: a role
RT for Chk1 in the intra-S phase checkpoint monitoring replication origin
RT firing.";
RL J. Cell Biol. 154:913-923(2001).
RN [10]
RP PHOSPHORYLATION SITES SER-317 AND SER-345, AND MUTAGENESIS OF ASP-130;
RP SER-317; SER-345; SER-357; SER-366 AND SER-468.
RX MEDLINE=21286906; PubMed=11390642;
RX DOI=10.1128/MCB.21.13.4129-4139.2001;
RA Zhao H., Piwnica-Worms H.;
RT "ATR-mediated checkpoint pathways regulate phosphorylation and
RT activation of human Chk1.";
RL Mol. Cell. Biol. 21:4129-4139(2001).
RN [11]
RP SUBSTRATE SPECIFICITY, AND MUTAGENESIS OF ASP-130.
RX PubMed=11821419; DOI=10.1074/jbc.M111705200;
RA O'Neill T., Giarratani L., Chen P., Iyer L., Lee C.-H., Bobiak M.,
RA Kanai F., Zhou B.-B., Chung J.H., Rathbun G.A.;
RT "Determination of substrate motifs for human Chk1 and hCds1/Chk2 by
RT the oriented peptide library approach.";
RL J. Biol. Chem. 277:16102-16115(2002).
RN [12]
RP ERRATUM.
RA O'Neill T., Giarratani L., Chen P., Iyer L., Lee C.-H., Bobiak M.,
RA Kanai F., Zhou B.-B., Chung J.H., Rathbun G.A.;
RL J. Biol. Chem. 277:35776-35777(2002).
RN [13]
RP FUNCTION, PHOSPHORYLATION SITES SER-317 AND SER-345, AND MUTAGENESIS
RP OF LYS-38.
RX PubMed=12446774; DOI=10.1128/MCB.22.24.8552-8561.2002;
RA Heffernan T.P., Simpson D.A., Frank A.R., Heinloth A.N., Paules R.S.,
RA Cordeiro-Stone M., Kaufmann W.K.;
RT "An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation
RT following UVC-induced DNA damage.";
RL Mol. Cell. Biol. 22:8552-8561(2002).
RN [14]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH BRCA1.
RX PubMed=11836499; DOI=10.1038/ng837;
RA Yarden R.I., Pardo-Reoyo S., Sgagias M., Cowan K.H., Brody L.C.;
RT "BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon
RT DNA damage.";
RL Nat. Genet. 30:285-289(2002).
RN [15]
RP FUNCTION.
RX PubMed=12399544; DOI=10.1073/pnas.182557299;
RA Zhao H., Watkins J.L., Piwnica-Worms H.;
RT "Disruption of the checkpoint kinase 1/cell division cycle 25A pathway
RT abrogates ionizing radiation-induced S and G2 checkpoints.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:14795-14800(2002).
RN [16]
RP FUNCTION, PHOSPHORYLATION SITES SER-317 AND SER-345, AND MUTAGENESIS
RP OF SER-317 AND SER-345.
RX PubMed=12676583; DOI=10.1016/S1535-6108(03)00048-5;
RA Soerensen C.S., Syljuaesen R.G., Falck J., Schroeder T.,
RA Roennstrand L., Khanna K.K., Zhou B.-B., Bartek J., Lukas J.;
RT "Chk1 regulates the S phase checkpoint by coupling the physiological
RT turnover and ionizing radiation-induced accelerated proteolysis of
RT Cdc25A.";
RL Cancer Cell 3:247-258(2003).
RN [17]
RP FUNCTION, AND PHOSPHORYLATION SITE SER-317.
RX MEDLINE=22546651; PubMed=12660173; DOI=10.1093/emboj/cdg151;
RA Groth A., Lukas J., Nigg E.A., Sillje H.H.W., Wernstedt C., Bartek J.,
RA Hansen K.;
RT "Human tousled like kinases are targeted by an ATM- and Chk1-dependent
RT DNA damage checkpoint.";
RL EMBO J. 22:1676-1687(2003).
RN [18]
RP FUNCTION, AND MUTAGENESIS OF ASP-130.
RX PubMed=14681206; DOI=10.1101/gad.1157503;
RA Jin J., Shirogane T., Xu L., Nalepa G., Qin J., Elledge S.J.,
RA Harper J.W.;
RT "SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A
RT protein phosphatase.";
RL Genes Dev. 17:3062-3074(2003).
RN [19]
RP PHOSPHORYLATION SITE SER-317, AND MUTAGENESIS OF ASP-130; SER-317 AND
RP SER-345.
RX PubMed=12588868; DOI=10.1074/jbc.M210862200;
RA Gatei M., Sloper K., Soerensen C., Syljuaesen R., Falck J., Hobson K.,
RA Savage K., Lukas J., Zhou B.-B., Bartek J., Khanna K.K.;
RT "Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent
RT phosphorylation of Chk1 on ser-317 in response to ionizing
RT radiation.";
RL J. Biol. Chem. 278:14806-14811(2003).
RN [20]
RP FUNCTION, AND PHOSPHORYLATION SITE SER-345.
RX PubMed=12676925; DOI=10.1074/jbc.M300229200;
RA Xiao Z., Chen Z., Gunasekera A.H., Sowin T.J., Rosenberg S.H.,
RA Fesik S., Zhang H.;
RT "Chk1 mediates S and G2 arrests through Cdc25A degradation in response
RT to DNA-damaging agents.";
RL J. Biol. Chem. 278:21767-21773(2003).
RN [21]
RP INTERACTIONS WITH YWHAZ AND XPO1, SUBCELLULAR LOCATION, ASSOCIATION
RP WITH CHROMATIN, PHOSPHORYLATION SITES SER-317 AND SER-345, AND
RP MUTAGENESIS OF SER-317; PHE-344; SER-345 AND MET-353.
RX PubMed=12676962; DOI=10.1074/jbc.M300070200;
RA Jiang K., Pereira E., Maxfield M., Russell B., Goudelock D.M.,
RA Sanchez Y.;
RT "Regulation of Chk1 includes chromatin association and 14-3-3 binding
RT following phosphorylation on ser-345.";
RL J. Biol. Chem. 278:25207-25217(2003).
RN [22]
RP FUNCTION.
RX PubMed=12759351; DOI=10.1074/jbc.M302704200;
RA Hassepass I., Voit R., Hoffmann I.;
RT "Phosphorylation at serine 75 is required for UV-mediated degradation
RT of human Cdc25A phosphatase at the S-phase checkpoint.";
RL J. Biol. Chem. 278:29824-29829(2003).
RN [23]
RP INTERACTION WITH CLSPN.
RX PubMed=12766152; DOI=10.1074/jbc.M301136200;
RA Chini C.C.S., Chen J.;
RT "Human claspin is required for replication checkpoint control.";
RL J. Biol. Chem. 278:30057-30062(2003).
RN [24]
RP FUNCTION.
RX PubMed=14559997; DOI=10.1128/MCB.23.21.7488-7497.2003;
RA Chen M.-S., Ryan C.E., Piwnica-Worms H.;
RT "Chk1 kinase negatively regulates mitotic function of Cdc25A
RT phosphatase through 14-3-3 binding.";
RL Mol. Cell. Biol. 23:7488-7497(2003).
RN [25]
RP FUNCTION.
RX PubMed=12955071; DOI=10.1038/sj.onc.1206691;
RA Krause D.R., Jonnalagadda J.C., Gatei M.H., Sillje H.H.W., Zhou B.-B.,
RA Nigg E.A., Khanna K.;
RT "Suppression of tousled-like kinase activity after DNA damage or
RT replication block requires ATM, NBS1 and Chk1.";
RL Oncogene 22:5927-5937(2003).
RN [26]
RP PHOSPHORYLATION SITE SER-317.
RX PubMed=14657349; DOI=10.1073/pnas.2536810100;
RA Wang Y., Qin J.;
RT "MSH2 and ATR form a signaling module and regulate two branches of the
RT damage response to DNA methylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:15387-15392(2003).
RN [27]
RP FUNCTION, AND PHOSPHORYLATION SITE SER-345.
RX PubMed=14988723; DOI=10.1038/sj.emboj.7600113;
RA Pichierri P., Rosselli F.;
RT "The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and
RT ATR-NBS1-FANCD2 pathways.";
RL EMBO J. 23:1178-1187(2004).
RN [28]
RP DOMAIN, MITOTIC PHOSPHORYLATION, PHOSPHORYLATION SITE SER-345, AND
RP MUTAGENESIS OF LYS-38.
RX PubMed=14681223; DOI=10.1074/jbc.M312215200;
RA Ng C.-P., Lee H.C., Ho C.W., Arooz T., Siu W.Y., Lau A., Poon R.Y.C.;
RT "Differential mode of regulation of the checkpoint kinases CHK1 and
RT CHK2 by their regulatory domains.";
RL J. Biol. Chem. 279:8808-8819(2004).
RN [29]
RP FUNCTION, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-130.
RX PubMed=15311285; DOI=10.1038/ncb1165;
RA Kraemer A., Mailand N., Lukas C., Syljuaesen R.G., Wilkinson C.J.,
RA Nigg E.A., Bartek J., Lukas J.;
RT "Centrosome-associated Chk1 prevents premature activation of cyclin-B-
RT Cdk1 kinase.";
RL Nat. Cell Biol. 6:884-891(2004).
RN [30]
RP INTERACTION WITH CLSPN, AND PHOSPHORYLATION SITES SER-296; SER-317 AND
RP SER-345.
RX PubMed=15707391; DOI=10.1042/BJ20041966;
RA Clarke C.A.L., Clarke P.R.;
RT "DNA-dependent phosphorylation of Chk1 and claspin in a human cell-
RT free system.";
RL Biochem. J. 388:705-712(2005).
RN [31]
RP SUBCELLULAR LOCATION.
RX PubMed=15710331; DOI=10.1016/j.ccr.2005.01.009;
RA Puc J., Keniry M., Li H.S., Pandita T.K., Choudhury A.D., Memeo L.,
RA Mansukhani M., Murty V.V.V.S., Gaciong Z., Meek S.E.M.,
RA Piwnica-Worms H., Hibshoosh H., Parsons R.;
RT "Lack of PTEN sequesters CHK1 and initiates genetic instability.";
RL Cancer Cell 7:193-204(2005).
RN [32]
RP INTERACTION WITH PPM1D, AND PHOSPHORYLATION SITES SER-317 AND SER-345.
RX PubMed=15870257; DOI=10.1101/gad.1291305;
RA Lu X., Nannenga B., Donehower L.A.;
RT "PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle
RT checkpoints.";
RL Genes Dev. 19:1162-1174(2005).
RN [33]
RP FUNCTION.
RX PubMed=15659650; DOI=10.1091/mbc.E04-08-0689;
RA Ou Y.-H., Chung P.-H., Sun T.-P., Shieh S.-Y.;
RT "p53 C-terminal phosphorylation by CHK1 and CHK2 participates in the
RT regulation of DNA-damage-induced C-terminal acetylation.";
RL Mol. Biol. Cell 16:1684-1695(2005).
RN [34]
RP FUNCTION, INTERACTION WITH RAD51, AND MUTAGENESIS OF SER-317 AND
RP SER-345.
RX PubMed=15665856; DOI=10.1038/ncb1212;
RA Soerensen C.S., Hansen L.T., Dziegielewski J., Syljuaesen R.G.,
RA Lundin C., Bartek J., Helleday T.;
RT "The cell-cycle checkpoint kinase Chk1 is required for mammalian
RT homologous recombination repair.";
RL Nat. Cell Biol. 7:195-201(2005).
RN [35]
RP FUNCTION, AND PHOSPHORYLATION SITE SER-345.
RX PubMed=15650047; DOI=10.1073/pnas.0409130102;
RA Huang X., Tran T., Zhang L., Hatcher R., Zhang P.;
RT "DNA damage-induced mitotic catastrophe is mediated by the Chk1-
RT dependent mitotic exit DNA damage checkpoint.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:1065-1070(2005).
RN [36]
RP X-RAY CRYSTALLOGRAPHY (1.7 ANGSTROMS) OF 1-289.
RX PubMed=10761933; DOI=10.1016/S0092-8674(00)80704-7;
RA Chen P., Luo C., Deng Y., Ryan K., Register J., Margosiak S.,
RA Tempczyk-Russell A., Nguyen B., Myers P., Lundgren K., Kan C.-C.,
RA O'Connor P.M.;
RT "The 1.7 A crystal structure of human cell cycle checkpoint kinase
RT Chk1: implications for Chk1 regulation.";
RL Cell 100:681-692(2000).
RN [37]
RP X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS) OF 1-289.
RX PubMed=12244092; DOI=10.1074/jbc.M201233200;
RA Zhao B., Bower M.J., McDevitt P.J., Zhao H., Davis S.T.,
RA Johanson K.O., Green S.M., Concha N.O., Zhou B.-B.S.;
RT "Structural basis for Chk1 inhibition by UCN-01.";
RL J. Biol. Chem. 277:46609-46615(2002).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS) OF 1-289.
RX PubMed=15974586; DOI=10.1021/jm049022c;
RA Foloppe N., Fisher L.M., Howes R., Kierstan P., Potter A.,
RA Robertson A.G.S., Surgenor A.E.;
RT "Structure-based design of novel Chk1 inhibitors: insights into
RT hydrogen bonding and protein-ligand affinity.";
RL J. Med. Chem. 48:4332-4345(2005).
Feature:
CHAIN 1 476 Serine/threonine-protein kinase Chk1.
/FTId=PRO_0000085848.
DOMAIN 9 265 Protein kinase.
NP_BIND 15 23 ATP (By similarity).
REGION 391 476 Autoinhibitory region.
ACT_SITE 130 130 Proton acceptor.
BINDING 38 38 ATP (By similarity).
MOD_RES 280 280 Phosphoserine (by PKB/AKT1) (By
similarity).
MOD_RES 296 296 Phosphoserine.
MOD_RES 317 317 Phosphoserine (by ATM and ATR).
MOD_RES 345 345 Phosphoserine (by ATM and ATR).
VARIANT 156 156 R -> Q (in dbSNP:3731410).
/FTId=VAR_021123.
VARIANT 471 471 V -> I (in dbSNP:506504).
/FTId=VAR_024571.
MUTAGEN 38 38 K->R: Abolishes kinase activity.
MUTAGEN 130 130 D->A: Abolishes kinase activity.
MUTAGEN 317 317 S->A: Abrogates interaction with RAD51;
when associated with A-345. Reduces
phosphorylation and impairs activation by
hydroxyurea and ionizing radiation.
Abrogates nuclear retention upon
checkpoint activation.
MUTAGEN 317 317 S->E: Enhances interaction with RAD51;
when associated with E-345.
MUTAGEN 344 344 F->A: Impairs nuclear export.
MUTAGEN 345 345 S->A: Abrogates interaction with RAD51;
when associated with A-317. Reduces
phosphorylation and impairs activation by
hydroxyurea and ionizing radiation.
Impairs interaction with YWHAZ which is
required for nuclear retention after
checkpoint activation.
MUTAGEN 345 345 S->E: Enhances interaction with RAD51;
when associated with E-317.
MUTAGEN 353 353 M->A: Impairs nuclear export.
MUTAGEN 357 357 S->A: No effect on phosphorylation
induced by hydroxyurea.
MUTAGEN 366 366 S->A: No effect on phosphorylation
induced by hydroxyurea.
MUTAGEN 468 468 S->A: No effect on phosphorylation
induced by hydroxyurea.
HELIX 4 7
STRAND 9 16
TURN 19 20
STRAND 22 28
TURN 29 31
STRAND 34 41
TURN 42 43
HELIX 49 61
TURN 65 66
STRAND 67 67
STRAND 70 74
TURN 77 78
STRAND 79 85
TURN 88 89
STRAND 90 91
HELIX 92 95
STRAND 96 97
TURN 98 100
STRAND 101 101
HELIX 104 123
TURN 124 125
STRAND 126 127
STRAND 129 129
STRAND 132 132
HELIX 133 135
STRAND 136 138
TURN 140 141
STRAND 144 146
TURN 150 151
STRAND 153 154
STRAND 156 157
TURN 158 159
STRAND 160 161
STRAND 164 164
STRAND 169 169
HELIX 171 173
STRAND 174 174
HELIX 176 180
STRAND 182 182
STRAND 184 184
HELIX 186 203
STRAND 204 205
STRAND 207 207
STRAND 209 211
TURN 213 214
HELIX 216 222
TURN 223 224
TURN 226 227
STRAND 228 228
TURN 229 230
HELIX 231 233
STRAND 234 234
STRAND 236 236
HELIX 237 245
STRAND 246 246
STRAND 248 249
TURN 250 252
STRAND 253 253
HELIX 256 259
TURN 260 261
TURN 263 266
STRAND 273 274
Comments:
-!- FUNCTION: Required for checkpoint mediated cell cycle arrest in
response to DNA damage or the presence of unreplicated DNA. May
also negatively regulate cell cycle progression during unperturbed
cell cycles. Recognizes the substrate consensus sequence [R-X-X-
S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C.
Phosphorylation of CDC25A at Ser-178 and Thr-507 and
phosphorylation of CDC25C at Ser-216 creates binding sites for 14-
3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of
CDC25A at Ser-76, Ser-124, Ser-178, Ser-279 and Ser-293 promotes
proteolysis of CDC25A. Inhibition of CDC25 activity leads to
increased inhibitory tyrosine phosphorylation of CDK-cyclin
complexes and blocks cell cycle progression. Binds to and
phosphorylates RAD51 at Thr-309, which may enhance the association
of RAD51 with chromatin and promote DNA repair by homologous
recombination. Binds to and phosphorylates TLK1 at Ser-743, which
prevents the TLK1-dependent phosphorylation of the chromatin
assembly factor ASF1A. This may affect chromatin assembly during S
phase or DNA repair. May also phosphorylate multiple sites within
the C-terminus of TP53, which promotes activation of TP53 by
acetylation and enhances suppression of cellular proliferation.
-!- CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.
-!- SUBUNIT: Interacts with BRCA1, CLSPN, PPM1D, RAD51, XPO1/CRM1 and
YWHAZ/14-3-3 zeta.
-!- SUBCELLULAR LOCATION: Nuclear and cytoplasmic. Nuclear export is
mediated at least in part by XPO1/CRM1. Also localizes to the
centrosome specifically during interphase, where it may protect
centrosomal CDC2 kinase from inappropriate activation by
cytoplasmic CDC25B.
-!- TISSUE SPECIFICITY: Expressed ubiquitously with the most abundant
expression in thymus, testis, small intestine and colon.
-!- DOMAIN: The autoinhibitory region (AIR) inhibits the activity of
the kinase domain.
-!- PTM: Phosphorylated by ATR in a RAD17-dependent manner in response
to ultraviolet irradiation and inhibition of DNA replication.
Phosphorylated by ATM in response to ionizing irradiation. ATM and
ATR can both phosphorylate Ser-317 and Ser-345 and this results in
enhanced kinase activity. Phosphorylation at Ser-345 also
increases binding to 14-3-3 proteins and promotes nuclear
retention. Conversely, dephosphorylation at Ser-345 by PPM1D may
contribute to exit from checkpoint mediated cell cycle arrest. May
also be phosphorylated at Ser-280 by AKT1/PKB, which may promote
mono and/or diubiquitination. Also phosphorylated at undefined
residues during mitotic arrest, which results in decreased
activity.
-!- PTM: Ubiquitinated. Mono or diubiquitination promotes nuclear
exclusion (By similarity).
-!- SIMILARITY: Belongs to the Ser/Thr protein kinase family. NIM1
subfamily.
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Sequence length: 476
MAVPFVEDWD LVQTLGEGAY GEVQLAVNRV TEEAVAVKIV DMKRAVDCPE NIKKEICINK
MLNHENVVKF YGHRREGNIQ YLFLEYCSGG ELFDRIEPDI GMPEPDAQRF FHQLMAGVVY
LHGIGITHRD IKPENLLLDE RDNLKISDFG LATVFRYNNR ERLLNKMCGT LPYVAPELLK
RREFHAEPVD VWSCGIVLTA MLAGELPWDQ PSDSCQEYSD WKEKKTYLNP WKKIDSAPLA
LLHKILVENP SARITIPDIK KDRWYNKPLK KGAKRPRVTS GGVSESPSGF SKHIQSNLDF
SPVNSASSEE NVKYSSSQPE PRTGLSLWDT SPSYIDKLVQ GISFSQPTCP DHMLLNSQLL
GTPGSSQNPW QRLVKRMTRF FTKLDADKSY QCLKETCEKL GYQWKKSCMN QVTISTTDRR
NNKLIFKVNL LEMDDKILVD FRLSKGDGLE FKRHFLKIKG KLIDIVSSQK VWLPAT