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CHEK1 (CHK1)

Protein FULL name:

serine/threonine-protein kinase Chk1 [Homo sapiens].


Protein SHORT name:

CHK1


CHEK1 (CHK1) (Homo sapiens) is product of expression of CHEK1 gene.


CHEK1 (CHK1) is involved in:

DDS in Homo sapiens
     


Keywords:



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, FBXO6, PPM1D, RAD51, TIMELESS, XPO1/CRM1 and YWHAZ/14-3-3 zeta.

INTERACTION: Q9NY61:AATF; NbExp=1; IntAct=EBI-974488, EBI-372428; P38398:BRCA1; NbExp=1; IntAct=EBI-974488, EBI-349905; P30304:CDC25A; NbExp=1; IntAct=EBI-974488, EBI-747671; P30307:CDC25C; NbExp=2; IntAct=EBI-974488, EBI-974439; O35280:Chek1 (xeno); NbExp=1; IntAct=EBI-974488, EBI-2553137; Q9HAW4:CLSPN; NbExp=4; IntAct=EBI-974488, EBI-1369377; P08238:HSP90AB1; NbExp=1; IntAct=EBI-974488, EBI-352572; Q9UNS1:TIMELESS; NbExp=2; IntAct=EBI-974488, EBI-2212315;

SUBCELLULAR LOCATION: Nucleus. Cytoplasm. Cytoplasm, cytoskeleton, centrosome. Note=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 induces a change in the conformation of the protein, activates the kinase activity and is a prerequisite for interaction with FBXO6 and subsequent ubiquitination at Lys-436. 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). The activated form (phosphorylated on Ser-345) is polyubiquitinated at Lys-436 by some SCF-type E3 ubiquitin ligase complex containing FBXO6 promoting its degradation. Ubiquitination of activated form is required to insure that activated CHK1 does not accumulate as cells progress through S phase, or when replication forks encounter transient impediments during normal DNA replication.

SIMILARITY: Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. NIM1 subfamily.

SIMILARITY: Contains 1 protein kinase domain.

WEB RESOURCE: Name=NIEHS-SNPs; [LINK]


NCBI GenPept GI number(s): 166295192
Species: Homo sapiens

Links to other databases:

Database ID Link
Uniprot O14757 O14757
PFAM: - O14757 (Link - using uniprot id)
InterPro: - O14757 (Link - using uniprot id)
CATH: - -
SCOP: - -
PDB: - -


Protein sequence:
MAVPFVEDWDLVQTLGEGAYGEVQLAVNRVTEEAVAVKIVDMKRAVDCPE
NIKKEICINKMLNHENVVKFYGHRREGNIQYLFLEYCSGGELFDRIEPDI
GMPEPDAQRFFHQLMAGVVYLHGIGITHRDIKPENLLLDERDNLKISDFG
LATVFRYNNRERLLNKMCGTLPYVAPELLKRREFHAEPVDVWSCGIVLTA
MLAGELPWDQPSDSCQEYSDWKEKKTYLNPWKKIDSAPLALLHKILVENP
SARITIPDIKKDRWYNKPLKKGAKRPRVTSGGVSESPSGFSKHIQSNLDF
SPVNSASSEENVKYSSSQPEPRTGLSLWDTSPSYIDKLVQGISFSQPTCP
DHMLLNSQLLGTPGSSQNPWQRLVKRMTRFFTKLDADKSYQCLKETCEKL
GYQWKKSCMNQVTISTTDRRNNKLIFKVNLLEMDDKILVDFRLSKGDGLE
FKRHFLKIKGKLIDIVSSQKIWLPAT

CHEK1 (CHK1) (Homo sapiens) is able to recognize following damages:
References:

Title Authors Journal
Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Sanchez Y, Wong C, Thoma RS, Richman R, Wu Z, Piwnica-Worms H, Elledge SJ Science Sept. 5, 1997
Atm-dependent interactions of a mammalian chk1 homolog with meiotic chromosomes. Flaggs G, Plug AW, Dunks KM, Mundt KE, Ford JC, Quiggle MR, Taylor EM, Westphal CH, Ashley T, Hoekstra MF, Carr AM Curr Biol Dec. 1, 1997
The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Shieh SY, Ahn J, Tamai K, Taya Y, Prives C Genes Dev Jan. 1, 2000
The 1.7 A crystal structure of human cell cycle checkpoint kinase Chk1: implications for Chk1 regulation. Chen P, Luo C, Deng Y, Ryan K, Register J, Margosiak S, Tempczyk-Russell A, Nguyen B, Myers P, Lundgren K, Kan CC, O'Connor PM Cell March 17, 2000
Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium. Semba S, Ouyang H, Han SY, Kato Y, Horii A Int J Oncol April 1, 2000
Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Liu Q, Guntuku S, Cui XS, Matsuoka S, Cortez D, Tamai K, Luo G, Carattini-Rivera S, DeMayo F, Bradley A, Donehower LA, Elledge SJ Genes Dev June 15, 2000
ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Zhao H, Piwnica-Worms H Mol Cell Biol July 1, 2001
Activation of mammalian Chk1 during DNA replication arrest: a role for Chk1 in the intra-S phase checkpoint monitoring replication origin firing. Feijoo C, Hall-Jackson C, Wu R, Jenkins D, Leitch J, Gilbert DM, Smythe C J Cell Biol Sept. 3, 2001
BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase upon DNA damage. Yarden RI, Pardo-Reoyo S, Sgagias M, Cowan KH, Brody LC Nat Genet March 1, 2002
Determination of substrate motifs for human Chk1 and hCds1/Chk2 by the oriented peptide library approach. O'Neill T, Giarratani L, Chen P, Iyer L, Lee CH, Bobiak M, Kanai F, Zhou BB, Chung JH, Rathbun GA J Biol Chem May 3, 2002
Structural basis for Chk1 inhibition by UCN-01. Zhao B, Bower MJ, McDevitt PJ, Zhao H, Davis ST, Johanson KO, Green SM, Concha NO, Zhou BB J Biol Chem Nov. 1, 2002
Disruption of the checkpoint kinase 1/cell division cycle 25A pathway abrogates ionizing radiation-induced S and G2 checkpoints. Zhao H, Watkins JL, Piwnica-Worms H Proc Natl Acad Sci U S A Nov. 12, 2002
An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Heffernan TP, Simpson DA, Frank AR, Heinloth AN, Paules RS, Cordeiro-Stone M, Kaufmann WK Mol Cell Biol Dec. 1, 2002
Chk1 regulates the S phase checkpoint by coupling the physiological turnover and ionizing radiation-induced accelerated proteolysis of Cdc25A. Sorensen CS, Syljuasen RG, Falck J, Schroeder T, Ronnstrand L, Khanna KK, Zhou BB, Bartek J, Lukas J Cancer Cell March 1, 2003
Human Tousled like kinases are targeted by an ATM- and Chk1-dependent DNA damage checkpoint. Groth A, Lukas J, Nigg EA, Sillje HH, Wernstedt C, Bartek J, Hansen K EMBO J April 1, 2003
Ataxia-telangiectasia-mutated (ATM) and NBS1-dependent phosphorylation of Chk1 on Ser-317 in response to ionizing radiation. Gatei M, Sloper K, Sorensen C, Syljuasen R, Falck J, Hobson K, Savage K, Lukas J, Zhou BB, Bartek J, Khanna KK J Biol Chem April 25, 2003
Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents. Xiao Z, Chen Z, Gunasekera AH, Sowin TJ, Rosenberg SH, Fesik S, Zhang H J Biol Chem June 13, 2003
Regulation of Chk1 includes chromatin association and 14-3-3 binding following phosphorylation on Ser-345. Jiang K, Pereira E, Maxfield M, Russell B, Goudelock DM, Sanchez Y J Biol Chem July 4, 2003
Human claspin is required for replication checkpoint control. Chini CC, Chen J J Biol Chem Aug. 8, 2003
Phosphorylation at serine 75 is required for UV-mediated degradation of human Cdc25A phosphatase at the S-phase checkpoint. Hassepass I, Voit R, Hoffmann I J Biol Chem Aug. 8, 2003
Suppression of Tousled-like kinase activity after DNA damage or replication block requires ATM, NBS1 and Chk1. Krause DR, Jonnalagadda JC, Gatei MH, Sillje HH, Zhou BB, Nigg EA, Khanna K Oncogene Sept. 4, 2003
Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding. Chen MS, Ryan CE, Piwnica-Worms H Mol Cell Biol Nov. 1, 2003
SCFbeta-TRCP links Chk1 signaling to degradation of the Cdc25A protein phosphatase. Jin J, Shirogane T, Xu L, Nalepa G, Qin J, Elledge SJ, Harper JW Genes Dev Dec. 15, 2003
MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation. Wang Y, Qin J Proc Natl Acad Sci U S A Dec. 23, 2003
Complete sequencing and characterization of 21,243 full-length human cDNAs. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S Nat Genet Feb. 1, 2004
Differential mode of regulation of the checkpoint kinases CHK1 and CHK2 by their regulatory domains. Ng CP, Lee HC, Ho CW, Arooz T, Siu WY, Lau A, Poon RY J Biol Chem March 5, 2004
The DNA crosslink-induced S-phase checkpoint depends on ATR-CHK1 and ATR-NBS1-FANCD2 pathways. Pichierri P, Rosselli F EMBO J March 10, 2004
Centrosome-associated Chk1 prevents premature activation of cyclin-B-Cdk1 kinase. Kramer A, Mailand N, Lukas C, Syljuasen RG, Wilkinson CJ, Nigg EA, Bartek J, Lukas J Nat Cell Biol Sept. 1, 2004
The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J Genome Res Oct. 1, 2004
Lack of PTEN sequesters CHK1 and initiates genetic instability. Puc J, Keniry M, Li HS, Pandita TK, Choudhury AD, Memeo L, Mansukhani M, Murty VV, Gaciong Z, Meek SE, Piwnica-Worms H, Hibshoosh H, Parsons R Cancer Cell Jan. 1, 2005
The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Sorensen CS, Hansen LT, Dziegielewski J, Syljuasen RG, Lundin C, Bartek J, Helleday T Nat Cell Biol Jan. 1, 2005
DNA damage-induced mitotic catastrophe is mediated by the Chk1-dependent mitotic exit DNA damage checkpoint. Huang X, Tran T, Zhang L, Hatcher R, Zhang P Proc Natl Acad Sci U S A Feb. 25, 2005
p53 C-terminal phosphorylation by CHK1 and CHK2 participates in the regulation of DNA-damage-induced C-terminal acetylation. Ou YH, Chung PH, Sun TP, Shieh SY Mol Biol Cell April 1, 2005
Coupling of human circadian and cell cycles by the timeless protein. Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A Mol Cell Biol April 1, 2005
PPM1D dephosphorylates Chk1 and p53 and abrogates cell cycle checkpoints. Lu X, Nannenga B, Donehower LA Genes Dev May 15, 2005
DNA-dependent phosphorylation of Chk1 and Claspin in a human cell-free system. Clarke CA, Clarke PR Biochem J June 1, 2005
Structure-based design of novel Chk1 inhibitors: insights into hydrogen bonding and protein-ligand affinity. Foloppe N, Fisher LM, Howes R, Kierstan P, Potter A, Robertson AG, Surgenor AE J Med Chem June 1, 2005
Tryptic digestion of ubiquitin standards reveals an improved strategy for identifying ubiquitinated proteins by mass spectrometry. Denis NJ, Vasilescu J, Lambert JP, Smith JC, Figeys D Proteomics March 1, 2007
Patterns of somatic mutation in human cancer genomes. Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, Davies H, Teague J, Butler A, Stevens C, Edkins S, O'Meara S, Vastrik I, Schmidt EE, Avis T, Barthorpe S, Bhamra G, Buck G, Choudhury B, Clements J, Cole J, Dicks E, Forbes S, Gray K, Halliday K, Harrison R, Hills K, Hinton J, Jenkinson A, Jones D, Menzies A, Mironenko T, Perry J, Raine K, Richardson D, Shepherd R, Small A, Tofts C, Varian J, Webb T, West S, Widaa S, Yates A, Cahill DP, Louis DN, Goldstraw P, Nicholson AG, Brasseur F, Looijenga L, Weber BL, Chiew YE, DeFazio A, Greaves MF, Green AR, Campbell P, Birney E, Easton DF, Chenevix-Trench G, Tan MH, Khoo SK, Teh BT, Yuen ST, Leung SY, Wooster R, Futreal PA, Stratton MR Nature March 8, 2007
ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J, Bakalarski CE, Zhao Z, Solimini N, Lerenthal Y, Shiloh Y, Gygi SP, Elledge SJ Science May 25, 2007
A quantitative atlas of mitotic phosphorylation. Dephoure N, Zhou C, Villen J, Beausoleil SA, Bakalarski CE, Elledge SJ, Gygi SP Proc Natl Acad Sci U S A Aug. 5, 2008
Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M Mol Cell Aug. 8, 2008
Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Mayya V, Lundgren DH, Hwang SI, Rezaul K, Wu L, Eng JK, Rodionov V, Han DK Sci Signal Jan. 1, 2009
Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Gauci S, Helbig AO, Slijper M, Krijgsveld J, Heck AJ, Mohammed S Anal Chem June 1, 2009
Large-scale proteomics analysis of the human kinome. Oppermann FS, Gnad F, Olsen JV, Hornberger R, Greff Z, Keri G, Mann M, Daub H Mol Cell Proteomics July 1, 2009
The F box protein Fbx6 regulates Chk1 stability and cellular sensitivity to replication stress. Zhang YW, Brognard J, Coughlin C, You Z, Dolled-Filhart M, Aslanian A, Manning G, Abraham RT, Hunter T Mol Cell Aug. 28, 2009


Last modification of this entry: Oct. 12, 2010.

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