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ATR

Protein FULL name:

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


ATR (Homo sapiens) is product of expression of ATR gene.

Human diseases related to this protein:

ATR is involved in:

DDS in Homo sapiens
     


Keywords:



FUNCTION: Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates BRCA1, CHEK1, MCM2, RAD17, RPA2, SMC1 and TP53/p53, which collectively inhibit DNA replication and mitosis and promote DNA repair, recombination and apoptosis. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at sites of DNA damage, thereby regulating DNA damage response mechanism. Required for FANCD2 ubiquitination. Critical for maintenance of fragile site stability and efficient regulation of centrosome duplication.

CATALYTIC ACTIVITY: ATP + a protein = ADP + a phosphoprotein.

COFACTOR: Manganese.

ENZYME REGULATION: Activated by DNA and inhibited by BCR-ABL oncogene. Slightly activated by ATRIP. Inhibited by caffeine, wortmannin and LY294002.

SUBUNIT: Forms an heterodimer with ATRIP. Binds to DNA, and to UV- damaged DNA with higher affinity. Interacts with RAD17, MSH2 and HDAC2. Present in a complex containing ATRIP and RPA-coated single-stranded DNA. Present in a complex containing CHD4 and HDAC2. Interacts with BCR-ABL after genotoxic stress. Interacts with EEF1E1. This interaction is enhanced by UV irradiation. Interacts with CLSPN and CEP164. Interacts with TELO2 AND TTI1.

INTERACTION: Q9NY61:AATF; NbExp=1; IntAct=EBI-968983, EBI-372428; P16220:CREB1; NbExp=1; IntAct=EBI-968983, EBI-711855; P04637:TP53; NbExp=1; IntAct=EBI-968983, EBI-366083;

SUBCELLULAR LOCATION: Nucleus. Note=Depending on the cell type, it can also be found in PML nuclear bodies. Recruited to chromatin during S-phase. Redistributes to discrete nuclear foci upon DNA damage, hypoxia or replication fork stalling.

TISSUE SPECIFICITY: Ubiquitous, with highest expression in testis. Isoform 2 is found in pancreas, placenta and liver but not in heart, testis and ovary.

PTM: Phosphorylated; autophosphorylates in vitro.

DISEASE: Defects in ATR are a cause of Seckel syndrome type 1 (SCKL1) [MIM:210600]. SCKL1 is a rare autosomal recessive disorder characterized by growth retardation, microcephaly with mental retardation, and a characteristic 'bird-headed' facial appearance.

SIMILARITY: Belongs to the PI3/PI4-kinase family. ATM subfamily.

SIMILARITY: Contains 1 FAT domain.

SIMILARITY: Contains 1 FATC domain.

SIMILARITY: Contains 2 HEAT repeats.

SIMILARITY: Contains 1 PI3K/PI4K domain.

WEB RESOURCE: Name=GeneReviews; [LINK]


NCBI GenPept GI number(s): 157266317
Species: Homo sapiens

Links to other databases:

Database ID Link
Uniprot Q13535 Q13535
PFAM: - Q13535 (Link - using uniprot id)
InterPro: - Q13535 (Link - using uniprot id)
CATH: None  
SCOP: None  
PDB: - -


Protein sequence:
MGEHGLELASMIPALRELGSATPEEYNTVVQKPRQILCQFIDRILTDVNV
VAVELVKKTDSQPTSVMLLDFIQHIMKSSPLMFVNVSGSHEAKGSCIEFS
NWIITRLLRIAATPSCHLLHKKICEVICSLLFLFKSKSPAIFGVLTKELL
QLFEDLVYLHRRNVMGHAVEWPVVMSRFLSQLDEHMGYLQSAPLQLMSMQ
NLEFIEVTLLMVLTRIIAIVFFRRQELLLWQIGCVLLEYGSPKIKSLAIS
FLTELFQLGGLPAQPASTFFSSFLELLKHLVEMDTDQLKLYEEPLSKLIK
TLFPFEAEAYRNIEPVYLNMLLEKLCVMFEDGVLMRLKSDLLKAALCHLL
QYFLKFVPAGYESALQVRKVYVRNICKALLDVLGIEVDAEYLLGPLYAAL
KMESMEIIEEIQCQTQQENLSSNSDGISPKRRRLSSSLNPSKRAPKQTEE
IKHVDMNQKSILWSALKQKAESLQISLEYSGLKNPVIEMLEGIAVVLQLT
ALCTVHCSHQNMNCRTFKDCQHKSKKKPSVVITWMSLDFYTKVLKSCRSL
LESVQKLDLEATIDKVVKIYDALIYMQVNSSFEDHILEDLCGMLSLPWIY
SHSDDGCLKLTTFAANLLTLSCRISDSYSPQAQSRCVFLLTLFPRRIFLE
WRTAVYNWALQSSHEVIRASCVSGFFILLQQQNSCNRVPKILIDKVKDDS
DIVKKEFASILGQLVCTLHGMFYLTSSLTEPFSEHGHVDLFCRNLKATSQ
HECSSSQLKASVCKPFLFLLKKKIPSPVKLAFIDNLHHLCKHLDFREDET
DVKAVLGTLLNLMEDPDKDVRVAFSGNIKHILESLDSEDGFIKELFVLRM
KEAYTHAQISRNNELKDTLILTTGDIGRAAKGDLVPFALLHLLHCLLSKS
ASVSGAAYTEIRALVAAKSVKLQSFFSQYKKPICQFLVESLHSSQMTALP
NTPCQNADVRKQDVAHQREMALNTLSEIANVFDFPDLNRFLTRTLQVLLP
DLAAKASPAASALIRTLGKQLNVNRREILINNFKYIFSHLVCSCSKDELE
RALHYLKNETEIELGSLLRQDFQGLHNELLLRIGEHYQQVFNGLSILASF
ASSDDPYQGPRDIISPELMADYLQPKLLGILAFFNMQLLSSSVGIEDKKM
ALNSLMSLMKLMGPKHVSSVRVKMMTTLRTGLRFKDDFPELCCRAWDCFV
RCLDHACLGSLLSHVIVALLPLIHIQPKETAAIFHYLIIENRDAVQDFLH
EIYFLPDHPELKKIKAVLQEYRKETSESTDLQTTLQLSMKAIQHENVDVR
IHALTSLKETLYKNQEKLIKYATDSETVEPIISQLVTVLLKGCQDANSQA
RLLCGECLGELGAIDPGRLDFSTTETQGKDFTFVTGVEDSSFAYGLLMEL
TRAYLAYADNSRAQDSAAYAIQELLSIYDCREMETNGPGHQLWRRFPEHV
REILEPHLNTRYKSSQKSTDWSGVKKPIYLSKLGSNFAEWSASWAGYLIT
KVRHDLASKIFTCCSIMMKHDFKVTIYLLPHILVYVLLGCNQEDQQEVYA
EIMAVLKHDDQHTINTQDIASDLCQLSTQTVFSMLDHLTQWARHKFQALK
AEKCPHSKSNRNKVDSMVSTVDYEDYQSVTRFLDLIPQDTLAVASFRSKA
YTRAVMHFESFITEKKQNIQEHLGFLQKLYAAMHEPDGVAGVSAIRKAEP
SLKEQILEHESLGLLRDATACYDRAIQLEPDQIIHYHGVVKSMLGLGQLS
TVITQVNGVHANRSEWTDELNTYRVEAAWKLSQWDLVENYLAADGKSTTW
SVRLGQLLLSAKKRDITAFYDSLKLVRAEQIVPLSAASFERGSYQRGYEY
IVRLHMLCELEHSIKPLFQHSPGDSSQEDSLNWVARLEMTQNSYRAKEPI
LALRRALLSLNKRPDYNEMVGECWLQSARVARKAGHHQTAYNALLNAGES
RLAELYVERAKWLWSKGDVHQALIVLQKGVELCFPENETPPEGKNMLIHG
RAMLLVGRFMEETANFESNAIMKKYKDVTACLPEWEDGHFYLAKYYDKLM
PMVTDNKMEKQGDLIRYIVLHFGRSLQYGNQFIYQSMPRMLTLWLDYGTK
AYEWEKAGRSDRVQMRNDLGKINKVITEHTNYLAPYQFLTAFSQLISRIC
HSHDEVFVVLMEIIAKVFLAYPQQAMWMMTAVSKSSYPMRVNRCKEILNK
AIHMKKSLEKFVGDATRLTDKLLELCNKPVDGSSSTLSMSTHFKMLKKLV
EEATFSEILIPLQSVMIPTLPSILGTHANHASHEPFPGHWAYIAGFDDMV
EILASLQKPKKISLKGSDGKFYIMMCKPKDDLRKDCRLMEFNSLINKCLR
KDAESRRRELHIRTYAVIPLNDECGIIEWVNNTAGLRPILTKLYKEKGVY
MTGKELRQCMLPKSAALSEKLKVFREFLLPRHPPIFHEWFLRTFPDPTSW
YSSRSAYCRSTAVMSMVGYILGLGDRHGENILFDSLTGECVHVDFNCLFN
KGETFEVPEIVPFRLTHNMVNGMGPMGTEGLFRRACEVTMRLMRDQREPL
MSVLKTFLHDPLVEWSKPVKGHSKAPLNETGEVVNEKAKTHVLDIEQRLQ
GVIKTRNRVTGLPLSIEGHVHYLIQEATDENLLCQMYLGWTPYM

ATR (Homo sapiens) belongs to following protein families:
References:

Title Authors Journal
cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Cimprich KA, Shin TB, Keith CT, Schreiber SL Proc Natl Acad Sci U S A April 2, 1996
The Atr and Atm protein kinases associate with different sites along meiotically pairing chromosomes. Keegan KS, Holtzman DA, Plug AW, Christenson ER, Brainerd EE, Flaggs G, Bentley NJ, Taylor EM, Meyn MS, Moss SB, Carr AM, Ashley T, Hoekstra MF Genes Dev Oct. 1, 1996
The Schizosaccharomyces pombe rad3 checkpoint gene. Bentley NJ, Holtzman DA, Flaggs G, Keegan KS, DeMaggio A, Ford JC, Hoekstra M, Carr AM EMBO J Dec. 2, 1996
Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH EMBO J Feb. 2, 1998
Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Wright JA, Keegan KS, Herendeen DR, Bentley NJ, Carr AM, Hoekstra MF, Concannon P Proc Natl Acad Sci U S A June 23, 1998
Inhibition of phosphoinositide 3-kinase related kinases by the radiosensitizing agent wortmannin. Sarkaria JN, Tibbetts RS, Busby EC, Kennedy AP, Hill DE, Abraham RT Cancer Res Oct. 1, 1998
A role for ATR in the DNA damage-induced phosphorylation of p53. Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT Genes Dev Feb. 15, 1999
Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4. Schmidt DR, Schreiber SL Biochemistry Nov. 2, 1999
ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Hall-Jackson CA, Cross DA, Morrice N, Smythe C Oncogene Nov. 18, 1999
Substrate specificities and identification of putative substrates of ATM kinase family members. Kim ST, Lim DS, Canman CE, Kastan MB J Biol Chem Dec. 31, 1999
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
Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT Genes Dev Dec. 1, 2000
ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF Nature June 21, 2001
Evidence for alternate splicing within the mRNA transcript encoding the DNA damage response kinase ATR. Mannino JL, Kim W, Wernick M, Nguyen SV, Braquet R, Adamson AW, Den Z, Batzer MA, Collins CC, Brown KD Gene July 11, 2001
ATR and ATRIP: partners in checkpoint signaling. Cortez D, Guntuku S, Qin J, Elledge SJ Science Nov. 23, 2001
Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. Ward IM, Chen J J Biol Chem Dec. 21, 2001
Hypoxia links ATR and p53 through replication arrest. Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ Mol Cell Biol March 1, 2002
Preferential binding of ATR protein to UV-damaged DNA. Unsal-Kacmaz K, Makhov AM, Griffith JD, Sancar A Proc Natl Acad Sci U S A May 14, 2002
ATR regulates fragile site stability. Casper AM, Nghiem P, Arlt MF, Glover TW Cell Dec. 13, 2002
A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA Nat Genet April 1, 2003
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Zou L, Elledge SJ Science June 6, 2003
ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Barr SM, Leung CG, Chang EE, Cimprich KA Curr Biol June 17, 2003
Human claspin is required for replication checkpoint control. Chini CC, Chen J J Biol Chem Aug. 8, 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
Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Unsal-Kacmaz K, Sancar A Mol Cell Biol Jan. 1, 2004
BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint. Dierov J, Dierova R, Carroll M Cancer Cell March 1, 2004
UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. Ward IM, Minn K, Chen J J Biol Chem March 12, 2004
Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase. Dart DA, Adams KE, Akerman I, Lakin ND J Biol Chem April 16, 2004
Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Cortez D, Glick G, Elledge SJ Proc Natl Acad Sci U S A July 6, 2004
ATR couples FANCD2 monoubiquitination to the DNA-damage response. Andreassen PR, D'Andrea AD, Taniguchi T Genes Dev Aug. 15, 2004
Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Alderton GK, Joenje H, Varon R, Borglum AD, Jeggo PA, O'Driscoll M Hum Mol Genet Dec. 15, 2004
The haploinsufficient tumor suppressor p18 upregulates p53 via interactions with ATM/ATR. Park BJ, Kang JW, Lee SW, Choi SJ, Shin YK, Ahn YH, Choi YH, Choi D, Lee KS, Kim S Cell Feb. 28, 2005
Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage. Falck J, Coates J, Jackson SP Nature March 31, 2005
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
Improved titanium dioxide enrichment of phosphopeptides from HeLa cells and high confident phosphopeptide identification by cross-validation of MS/MS and MS/MS/MS spectra. Yu LR, Zhu Z, Chan KC, Issaq HJ, Dimitrov DS, Veenstra TD J Proteome Res Nov. 1, 2007
Cep164 is a mediator protein required for the maintenance of genomic stability through modulation of MDC1, RPA, and CHK1. Sivasubramaniam S, Sun X, Pan YR, Wang S, Lee EY Genes Dev March 1, 2008
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
Tti1 and Tel2 are critical factors in mammalian target of rapamycin complex assembly. Kaizuka T, Hara T, Oshiro N, Kikkawa U, Yonezawa K, Takehana K, Iemura S, Natsume T, Mizushima N J Biol Chem June 25, 2010


Last modification of this entry: Oct. 22, 2010.

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