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ATR (ataxia telangiectasia and Rad3 related)

Written2010-05Mary E Gagou, Mark Meuth
Institute for Cancer Studies, The University of Sheffield, Medical School, Beech Hill Road, Sheffield, S10 2RX, UK

(Note : for Links provided by Atlas : click)


Alias (NCBI)FRP1
HGNC Alias symbFRP1
HGNC Alias nameMEC1, mitosis entry checkpoint 1, homolog (S. cerevisiae)
HGNC Previous nameataxia telangiectasia and Rad3 related
LocusID (NCBI) 545
Atlas_Id 728
Location 3q23  [Link to chromosome band 3q23]
Location_base_pair Starts at 142449235 and ends at 142578733 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping ATR.png]
Local_order According to NCBI Map Viewer (ATR), genes (pseudogenes and hypothetical proteins have been excluded) flanking ATR in telomere to centromere direction on 3q23 are: SLC9A9 (solute carrier family 9 (sodium/hydrogen exchanger), member 9), CHST2 (carbohydrate (N-acetylglucosamine-6-O) sulfotransferase 2), SR140 (U2-associated SR140 protein), PAQR9 (progestin and adipo Q receptor family member IX), PCOLCE2 (procollagen C-endopeptidase enhancer 2), TRPC1 (transient receptor potential cation channel, subfamily C, member 1), PLS1 (plastin I (I isoform)), ATR.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
ADGRV1 (5q14.3)::ATR (3q23)ATR (3q23)::DBR1 (3q22.3)WWTR1 (3q25.1)::ATR (3q23)
XRN1 (3q23)::ATR (3q23)
Note ATR is a serine/threonine kinase and belongs to the phosphoinositide 3- kinase related protein kinases (PIKKs), particularly to ATM (ataxia telangiectasia mutated) subfamily. It functions to maintain genome integrity by stabilizing replication forks and by regulating cell cycle progression and DNA repair. ATR, in a complex with its regulatory partner ATRIP (ATR interacting protein), localises to stalled replication forks responding to a variety of types of replication stress and DNA damage. Recipients of ATR signalling are a plethora of substrates among them DNA damage protein sensors, mediators and effectors, DNA repair proteins, proteins of replisome and chromatin remodelling as well as centrosomal proteins. ATR function is essential for cell viability and disruptions of ATR signalling cause genomic instability. Mutations in ATR gene are rare and compatible with life only when hypomorphic or heterozygous. A clear link between disease and ATR gene mutation is the Seckel syndrome, while ATR has been proposed to serve as a haploinsufficient tumor suppressor in some types of cell deficiencies and its activation has been detected in most cancer chemotherapies.
See also the Deep Insight: Ataxia-Telangiectasia and variants.


Note The first human ATR cDNA full-length clone (originally named FRP1, FRAP-related protein 1) was isolated from a Jurkat T-cell cDNA library and identified by its significant homology to other members of the phosphatidylinositol kinase-related kinase (PIKK) family. Evidence for the existence of two alternative ATR transcripts, with differential tissue expression, in the non-catalytic domain has been reported, by using RT-PCR. Transcript variants utilizing alternative polyadenylation signals are also exist. ATR gene has recently been annotated in the Ensembl database.
  Intron/Exon structure of the ATR gene (ENSG00000175054). There are two transcript isoforms of this gene, with 47 and 46 exons, respectively, spanning to an area of 129.59 kb. Exons are illustrated with vertical lines and boxes (A, B). Diagram in panel B represents only the exons' structure. Direction of transcription is shown by an arrow. The 6th exon that is missing from ATR isoform 2 is indicated with an asterisk (A) or with blue colour box (B). Untranslated regions are in light pink, while coding regions are in deep pink. Start of translation (ATG) and stop codon (TGA) are also indicated.
Description 47 exons spanning to 129.59 kb.
Transcription Two isoforms: isoform ATR-201 (ENST00000350721) (8248 bp) includes all 47 exons, while isoform ATR-202 (ENST00000383101) (8056 bp) does not include exon 6, deleting 192 nt (64 codons) from the mRNA. The translation start site is in exon 1.


Note ATR and ATM function in an overlapping, but non-redundant fashion, phosphorylating many of the same substrates. However, and in contrast to ATM, ATR's function is essential for cell viability. ATR-deficiency at the organismal level affects normal development, tissue homeostasis, and ageing.
Description Isoform ATR-201 (ENSP00000343741): 2644 amino acids (predicted MW 301365.74 Da).
Isoform ATR-202 (ENSP00000372581): 2580 aa (predicted MW 294218.33 Da).
Biochemical studies of ATR protein do not distinguish between the two different isoforms.
ATR protein contains a PI3/4 kinase catalytic domain, 1 FAT domain, 1 FATC domain, 1 UME domain, and 2 HEAT repeats.
Expression Isoform 1 has ubiquitous expression with highest levels in testis. Isoform 2 has more specific expression (has found in pancreas, liver and placenta while is not detected in heart, testis and ovary).
Forced expression of ATR inhibits MyoD function, leading to loss of differentiation, as well as induces cell-cycle abnormalities (increased aneuploidy and elimination of IR-induced G1 arrest). Limited expression of ATR or overexpression of kinase dead forms of this protein increases cell sensitivity to a variety of DNA damage agents and replication inhibitors, such as ionizing radiation (IR), cis-platinum, hydroxy urea (HU), methylmethanesulfonate (MMS) and ultra violet (UV) irradiation, leading to significant losses in checkpoint control and cell viability. Loss of ATR results in DNA fragile site expression, a specific type of genomic instability.
Localisation In the nucleus, where it is recruited to chromatin during S-phase and redistributes to distinct foci upon DNA damage, stalling of replication forks with replication inhibitors or hypoxia. ATR has also been found in PML (promyetocytic leukaemia protein) nuclear bodies of some types of cells.
Kinase dead forms of ATR do not relocalize in response to IR and block nuclear translocation of RPA complex in a cell cycle-dependent manner.
Function ATR essential maintains genome integrity by serving multiple roles in the cellular response to DNA damage and endogenous replication stress. It signals to regulate the firing of replication origins, the repair of damaged replication forks and to prevent the premature mitotic entry. Moreover, it critically functions directly at the sites of stalled forks by stabilizing components of the replisome to ensure completion of replication during recovery of stalled forks.

ATR-mediated activation of S-phase checkpoint
ATR is activated during every S-phase and in response to many different types of damage, including double strand breaks (DSB), base adducts, crosslinks and replication stress. The structural requirement for ATR activation is a RPA-coated single-stranded DNA with a 5' double stranded primer junction. ATR recognition of the above DNA structure depends upon a protein co-factor, ATRIP (ATR-interacting protein), that regulates ATR localization and activation. The activity of ATR-ATRIP complex is directly stimulated by TOPBP1 (DNA topoisomerase II binding protein 1), which recruitment to DNA is facilitated by the 9-1-1 (Rad9-Rad1-Hus1) checkpoint clamp.
Activated ATR signals to coordinate cell cycle transitions and repair through the phosphorylation of numerous of substrates including RAD17, p53, TopBP1 (via a feed-forward signalling loop that amplifies ATR-mediated signals), the mediator protein CEP164 and the downstream effector Chk1 (checkpoint kinase 1), which is the best characterized target of the ATR activity. Recombination proteins BRCA1 (breast cancer susceptibility gene 1), WRN (Werner's syndrome helicase), and BLM (Bloom's syndrome helicase) are ATR sunstrates as well. ATR also phosphorylates the Fanconi-anemia protein FANCD2 to regulate inter-strand crosslink repair as well as the nucleotide excision repair protein XPA to regulate its intracellular localization. Moreover, ATR interacts with the mismatch repair protein MSH2 (mutS homolog 2) to form a signalling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1). Upon replication stress ATR also phosphorylates the Ser-139 of H2AX/H2AFX, while is associated with the tyrosine kinase oncogene BCR-ABL after genotoxic stress.

ATR-mediated stabilization of replication forks
ATR has a crucial role in the maintenance of functional replication forks independent of its function in the activation of Rad53 (yeast homolog of checkpoint kinase 2). Among substrates of ATR on the replication forks are the proteins RPA1, RPA2, MCM2-7 (minichromosome maintenance 2-7) complex, MCM10, PCNA, replication factor C, Tim (Timeless)-Tipin complex, SMARCAL1 (HARP)-a SNF2 ATP-dependent annealing helicase, and several polymerases, such as Pol alpha and Pol epsilon. Furthermore, a key target of ATR-ATRIP complex is Claspin, and is important both for S-phase checkpoint activation (via regulation of Chk1 phosphorylation) but also for replication forks stabilization (via interactions with Pol epsilon) even in normal cycling cells. ATR is found also associated with two components of the nucleosome remodelling and deacetylating complex, the chromodomain-helicase-DNA-binding protein 4 (CHD4) and the histone-deacetylase-2 (HDAC2).
ATR also functions to stabilize fragile sites. In effect of all the above, the ATR's essential function for cell viability may be to respond to abundant sources of replication stress in normal cycling cells as well as after exposure to DNA damage agents.

ATR implication in centrosomal function via:
(a) Direct interaction with NBS1 (Nijmegen breakage syndrome 1) and BRCA1 pathway.
(b) Signalling to Chk1 and control of centrosome overduplication after DNA damage.
(c) Direct phosphorylation and delocalization from centrosome of CEP63 in the presence of chromosomal breaks.

Homology According to HomoloGene (NCBI), homologs of the human ATR gene (NP_001175.2, 2644 aa) are the followings:
- Chimpanzee (Pan troglodytes) XP_516792.2, 2646 aa
- Dog (Canis lupus familiaris) XP_534295.2, 2644 aa
- Cattle (Bos taurus) XP_581054.3, 2644 aa
- Rat (Rattus norvegicus) XP_001062084.1, 2166 aa
- Zebrafish (Danio rerio) XP_696163.3, 2638 aa


Somatic Single nucleotide substitutions have been described in various types of carcinomas at total frequency 2%, mostly in heterozygous form. In particular, missense mutations have been found in the PI3/4 kinase catalytic domain and in FAT domain of breast and lung cancers respectively. Coding silent mutations have also been detected in carcinomas of stomach, breast, skin and central nervous system.

Implicated in

Entity ATR haploinsufficiency in mismatch repair (MMR)-deficient cancers
Note Homozygous null mutations of ATR have not been reported in human cancers even in late-stage malignant cells and it is unlikely to exist given that mutations in both alleles of ATR gene lead to cell lethality. However, ATR gene has a potential increased susceptibility to somatic mutations in tumors with defective MMR, due to the presence of an A10 mononucleotide repeat in the exon 10 protein coding region. In particular, clinical reports have demonstrated that ATR is heterozygously mutated in certain types of tumors with mismatch repair deficiencies, including malignancies of the colon, the stomach and the endometrium. Although, it is not well understood how these mutations could contribute to the tumorigenic process, lines of evidence suggest that ATR serves as a haploinsufficient tumor suppressor in mismatch repair-deficient cells. Disruption of a single ATR allele gene in MLH1-deficient background significantly increases fragile site expression, chromosomal amplifications and rearrangements. The above chromosomal instability accompanied by hypersensitivity to genotoxic stress agents, such as hydroxyurea. Furthermore, mice with ATR+/- MLH1-/- genotype are more prone to early tumor development compared with ATR+/- or MLH1-/- counterparts. More recently has been reported that the combined ATR haploinsufficiency and MMR-deficiency that lead to chromosomal instability in colon cancer cells are also enhance the sensitivity of these cells to chemotherapeutic agent 5-fluorouracil, a standard treatment for colorectal cancers. The mechanism by which this occurs remains unclear. However, some findings suggest that MMR-deficient cells with partial reduced ATR activity are more prone to formation of DNA double strand breaks (DSBs). Additionally, partial inhibition of ATR has been reported to be significant for treatment of patients with high-microsatellite instability (MSI, a class of genomic instability clinically distinct from chromosome instability that is the result of mutations in MMR machinery) colorectal tumors increasing the disease-free survival time.
Prognosis Recent works have demonstrated that high-MSI endometrioid endometrial cancers harboring ATR mutations have worse survival compared to ATR wild-type high-MSI tumors, suggesting that the last ones might also have an improved prognosis compared to microsatellite stable (MSS) endometrial tumors. However, the prognostic significance of ATR mutations in MMR deficient cancers remains to be clarified.
Cytogenetics ATR partial knockdown in colon cancer cell lines with defective MMR leads to the formation of chromosomal breaks and gaps, chromosome bridges and micronuclei, as well as to the formation of supernumerary centrosomes.
Entity ATR-mutated Seckel syndrome (ATR-SS)
Note Seckel syndrome is a rare autosomal recessive disorder characterised by severe intrauterine growth retardation, profound microcephaly, dwarfism, mental retardation and isolated skeletal abnormalities. At least four distinct Seckel syndrome-causative genomic loci (Skl 1-4) have been identified but only two genetic defects are known in this disorder. Both of them impacting on ATR-dependent DNA damage signalling. The first identified defect was in ATR gene itself, concerning a hypomorphic single synonymous mutation (A>G 2101) that caused aberrant splicing of ATR. Pericentrin (PCNT), a core structural component of centrosomes, has also been identified as Seckel syndrome-causative gene.
Cytogenetics Cells from ATR-SS patients exhibit increased sensitivity to DNA replication fork stalling (measured as nuclear fragmentation and micronucleus formation), impaired phosphorylation of ATR substrates, defective G2/M arrest and supernumerous mitotic centrosomes.
Impaired ATR signalling is also characteristic of cells derived from other disorders with microcephaly and growth delay such as pericentrin-mutated Seckel syndrome (PCNT-SS), primary autosomal recessive microcephaly (MCPH) and Nijmegen breakage syndrome.


Regulation of mitotic entry by microcephalin and its overlap with ATR signalling.
Alderton GK, Galbiati L, Griffith E, Surinya KH, Neitzel H, Jackson AP, Jeggo PA, O'Driscoll M.
Nat Cell Biol. 2006 Jul;8(7):725-33. Epub 2006 Jun 18.
PMID 16783362
ATR couples FANCD2 monoubiquitination to the DNA-damage response.
Andreassen PR, D'Andrea AD, Taniguchi T.
Genes Dev. 2004 Aug 15;18(16):1958-63.
PMID 15314022
The annealing helicase SMARCAL1 maintains genome integrity at stalled replication forks.
Bansbach CE, Betous R, Lovejoy CA, Glick GG, Cortez D.
Genes Dev. 2009 Oct 15;23(20):2405-14. Epub 2009 Sep 30.
PMID 19793861
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. 2001 Jun 21;411(6840):969-74.
PMID 11418864
ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation.
Barr SM, Leung CG, Chang EE, Cimprich KA.
Curr Biol. 2003 Jun 17;13(12):1047-51.
PMID 12814551
DNA damage induces Chk1-dependent centrosome amplification.
Bourke E, Dodson H, Merdes A, Cuffe L, Zachos G, Walker M, Gillespie D, Morrison CG.
EMBO Rep. 2007 Jun;8(6):603-9. Epub 2007 Apr 27.
PMID 17468739
ATR disruption leads to chromosomal fragmentation and early embryonic lethality.
Brown EJ, Baltimore D.
Genes Dev. 2000 Feb 15;14(4):397-402.
PMID 10691732
Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint.
Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA.
Genes Dev. 2005 May 1;19(9):1040-52. Epub 2005 Apr 15.
PMID 15833913
ATR regulates fragile site stability.
Casper AM, Nghiem P, Arlt MF, Glover TW.
Cell. 2002 Dec 13;111(6):779-89.
PMID 12526805
Human claspin is required for replication checkpoint control.
Chini CC, Chen J.
J Biol Chem. 2003 Aug 8;278(32):30057-62. Epub 2003 May 24.
PMID 12766152
ATR: an essential regulator of genome integrity.
Cimprich KA, Cortez D.
Nat Rev Mol Cell Biol. 2008 Aug;9(8):616-27. Epub 2008 Jul 2. (REVIEW)
PMID 18594563
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. 1998 Jan 2;17(1):159-69.
PMID 9427750
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. 2004 Jul 6;101(27):10078-83. Epub 2004 Jun 21.
PMID 15210935
ATR and ATRIP: partners in checkpoint signaling.
Cortez D, Guntuku S, Qin J, Elledge SJ.
Science. 2001 Nov 23;294(5547):1713-6.
PMID 11721054
Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase.
Dart DA, Adams KE, Akerman I, Lakin ND.
J Biol Chem. 2004 Apr 16;279(16):16433-40. Epub 2004 Feb 9.
PMID 14871897
BCR/ABL translocates to the nucleus and disrupts an ATR-dependent intra-S phase checkpoint.
Dierov J, Dierova R, Carroll M.
Cancer Cell. 2004 Mar;5(3):275-85.
PMID 15050919
Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage.
Falck J, Coates J, Jackson SP.
Nature. 2005 Mar 31;434(7033):605-11. Epub 2005 Mar 2.
PMID 15758953
ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background.
Fang Y, Tsao CC, Goodman BK, Furumai R, Tirado CA, Abraham RT, Wang XF.
EMBO J. 2004 Aug 4;23(15):3164-74. Epub 2004 Jul 29.
PMID 15282542
ATR/Mec1: coordinating fork stability and repair.
Friedel AM, Pike BL, Gasser SM.
Curr Opin Cell Biol. 2009 Apr;21(2):237-44. Epub 2009 Feb 21. (REVIEW)
PMID 19230642
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. 2007 Mar 8;446(7132):153-8.
PMID 17344846
Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling.
Griffith E, Walker S, Martin CA, Vagnarelli P, Stiff T, Vernay B, Al Sanna N, Saggar A, Hamel B, Earnshaw WC, Jeggo PA, Jackson AP, O'Driscoll M.
Nat Genet. 2008 Feb;40(2):232-6. Epub 2007 Dec 23.
PMID 18157127
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. 1999 Nov 18;18(48):6707-13.
PMID 10597277
Hypoxia links ATR and p53 through replication arrest.
Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ.
Mol Cell Biol. 2002 Mar;22(6):1834-43.
PMID 11865061
Reduced ATR or Chk1 expression leads to chromosome instability and chemosensitization of mismatch repair-deficient colorectal cancer cells.
Jardim MJ, Wang Q, Furumai R, Wakeman T, Goodman BK, Wang XF.
Mol Biol Cell. 2009 Sep;20(17):3801-9. Epub 2009 Jul 1.
PMID 19570909
ATR mutations in endometrial cancer: a window into the role of mismatch repair defects.
Kauff ND.
J Clin Oncol. 2009 Jul 1;27(19):3077-8. Epub 2009 May 26. (REVIEW)
PMID 19470916
Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency.
Kerzendorfer C, O'Driscoll M.
DNA Repair (Amst). 2009 Sep 2;8(9):1139-52. Epub 2009 May 26. (REVIEW)
PMID 19473885
Substrate specificities and identification of putative substrates of ATM kinase family members.
Kim ST, Lim DS, Canman CE, Kastan MB.
J Biol Chem. 1999 Dec 31;274(53):37538-43.
PMID 10608806
Mutations in the ataxia telangiectasia and rad3-related-checkpoint kinase 1 DNA damage response axis in colon cancers.
Lewis KA, Bakkum-Gamez J, Loewen R, French AJ, Thibodeau SN, Cliby WA.
Genes Chromosomes Cancer. 2007 Dec;46(12):1061-8.
PMID 17879369
Heterozygous ATR mutations in mismatch repair-deficient cancer cells have functional significance.
Lewis KA, Mullany S, Thomas B, Chien J, Loewen R, Shridhar V, Cliby WA.
Cancer Res. 2005 Aug 15;65(16):7091-5.
PMID 16103057
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. 2000 Jun 15;14(12):1448-59.
PMID 10859164
Mrc1 and DNA polymerase epsilon function together in linking DNA replication and the S phase checkpoint.
Lou H, Komata M, Katou Y, Guan Z, Reis CC, Budd M, Shirahige K, Campbell JL.
Mol Cell. 2008 Oct 10;32(1):106-17.
PMID 18851837
Functional genomic screens identify CINP as a genome maintenance protein.
Lovejoy CA, Xu X, Bansbach CE, Glick GG, Zhao R, Ye F, Sirbu BM, Titus LC, Shyr Y, Cortez D.
Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19304-9. Epub 2009 Nov 4.
PMID 19889979
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. 2001 Jul 11;272(1-2):35-43.
PMID 11470508
Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability.
Menoyo A, Alazzouzi H, Espin E, Armengol M, Yamamoto H, Schwartz S Jr.
Cancer Res. 2001 Nov 1;61(21):7727-30.
PMID 11691784
Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability.
Miquel C, Jacob S, Grandjouan S, Aime A, Viguier J, Sabourin JC, Sarasin A, Duval A, Praz F.
Oncogene. 2007 Aug 30;26(40):5919-26. Epub 2007 Mar 26.
PMID 17384679
Mouse models for ATR deficiency.
O'Driscoll M.
DNA Repair (Amst). 2009 Nov 2;8(11):1333-7. Epub 2009 Sep 25. (REVIEW)
PMID 19782648
The ATR pathway: fine-tuning the fork.
Paulsen RD, Cimprich KA.
DNA Repair (Amst). 2007 Jul 1;6(7):953-66. Epub 2007 May 24. (REVIEW)
PMID 17531546
Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss.
Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G, Zediak VP, Velez M, Bhandoola A, Brown EJ.
Cell Stem Cell. 2007 Jun 7;1(1):113-26.
PMID 18371340
Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4.
Schmidt DR, Schreiber SL.
Biochemistry. 1999 Nov 2;38(44):14711-7.
PMID 10545197
Separate roles for the DNA damage checkpoint protein kinases in stabilizing DNA replication forks.
Segurado M, Diffley JF.
Genes Dev. 2008 Jul 1;22(13):1816-27.
PMID 18593882
Inactivation of the Nijmegen breakage syndrome gene leads to excess centrosome duplication via the ATR/BRCA1 pathway.
Shimada M, Sagae R, Kobayashi J, Habu T, Komatsu K.
Cancer Res. 2009 Mar 1;69(5):1768-75. Epub 2009 Feb 24.
PMID 19244116
ATR signaling at a glance.
Shiotani B, Zou L.
J Cell Sci. 2009 Feb 1;122(Pt 3):301-4.
PMID 19158338
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. 2008 Mar 1;22(5):587-600. Epub 2008 Feb 18.
PMID 18283122
An ATM- and ATR-dependent checkpoint inactivates spindle assembly by targeting CEP63.
Smith E, Dejsuphong D, Balestrini A, Hampel M, Lenz C, Takeda S, Vindigni A, Costanzo V.
Nat Cell Biol. 2009 Mar;11(3):278-85. Epub 2009 Feb 1.
PMID 19182792
Tim-Tipin dysfunction creates an indispensible reliance on the ATR-Chk1 pathway for continued DNA synthesis.
Smith KD, Fu MA, Brown EJ.
J Cell Biol. 2009 Oct 5;187(1):15-23.
PMID 19805627
Duplication of ATR inhibits MyoD, induces aneuploidy and eliminates radiation-induced G1 arrest.
Smith L, Liu SJ, Goodrich L, Jacobson D, Degnin C, Bentley N, Carr A, Flaggs G, Keegan K, Hoekstra M, Thayer MJ.
Nat Genet. 1998 May;19(1):39-46.
PMID 9590286
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. 2000 Dec 1;14(23):2989-3002.
PMID 11114888
Microcephalin and pericentrin regulate mitotic entry via centrosome-associated Chk1.
Tibelius A, Marhold J, Zentgraf H, Heilig CE, Neitzel H, Ducommun B, Rauch A, Ho AD, Bartek J, Kramer A.
J Cell Biol. 2009 Jun 29;185(7):1149-57. Epub 2009 Jun 22.
PMID 19546241
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. 2004 Feb;24(3):1292-300.
PMID 14729973
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. 2003 Dec 23;100(26):15387-92. Epub 2003 Dec 3.
PMID 14657349
Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress.
Ward IM, Chen J.
J Biol Chem. 2001 Dec 21;276(51):47759-62. Epub 2001 Oct 22.
PMID 11673449
UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress.
Ward IM, Minn K, Chen J.
J Biol Chem. 2004 Mar 12;279(11):9677-80. Epub 2004 Jan 23.
PMID 14742437
Loss of ataxia telangiectasia mutated- and Rad3-related function potentiates the effects of chemotherapeutic drugs on cancer cell survival.
Wilsker D, Bunz F.
Mol Cancer Ther. 2007 Apr;6(4):1406-13.
PMID 17431119
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. 1998 Jun 23;95(13):7445-50.
PMID 9636169
ATR mutation in endometrioid endometrial cancer is associated with poor clinical outcomes.
Zighelboim I, Schmidt AP, Gao F, Thaker PH, Powell MA, Rader JS, Gibb RK, Mutch DG, Goodfellow PJ.
J Clin Oncol. 2009 Jul 1;27(19):3091-6. Epub 2009 May 26.
PMID 19470935
Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes.
Zou L, Elledge SJ.
Science. 2003 Jun 6;300(5625):1542-8.
PMID 12791985


This paper should be referenced as such :
Gagou, ME ; Meuth, M
ATR (ataxia telangiectasia, Rad3 related)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(2):122-127.
Free journal version : [ pdf ]   [ DOI ]

Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  i(3)(q10) in non-Hodgkin's lymphoma (NHL)

External links


HGNC (Hugo)ATR   882
Entrez_Gene (NCBI)ATR    ATR serine/threonine kinase
AliasesFCTCS; FRP1; MEC1; SCKL; 
GeneCards (Weizmann)ATR
Ensembl hg19 (Hinxton)ENSG00000175054 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000175054 [Gene_View]  ENSG00000175054 [Sequence]  chr3:142449235-142578733 [Contig_View]  ATR [Vega]
ICGC DataPortalENSG00000175054
TCGA cBioPortalATR
Genatlas (Paris)ATR
SOURCE (Princeton)ATR
Genetics Home Reference (NIH)ATR
Genomic and cartography
GoldenPath hg38 (UCSC)ATR  -     chr3:142449235-142578733 -  3q23   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)ATR  -     3q23   [Description]    (hg19-Feb_2009)
GoldenPathATR - 3q23 [CytoView hg19]  ATR - 3q23 [CytoView hg38]
Genome Data Viewer NCBIATR [Mapview hg19]  
OMIM210600   601215   614564   
Gene and transcription
Genbank (Entrez)AB208847 AK307402 BE859077 DC346860 U49844
RefSeq transcript (Entrez)NM_001184 NM_001354579
Consensus coding sequences : CCDS (NCBI)ATR
Gene ExpressionATR [ NCBI-GEO ]   ATR [ EBI - ARRAY_EXPRESS ]   ATR [ SEEK ]   ATR [ MEM ]
Gene Expression Viewer (FireBrowse)ATR [ Firebrowse - Broad ]
GenevisibleExpression of ATR in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)545
GTEX Portal (Tissue expression)ATR
Human Protein AtlasENSG00000175054-ATR [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ13535   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ13535  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ13535
Catalytic activity : Enzyme2.7.11.1 [ Enzyme-Expasy ] [ IntEnz-EBI ] [ BRENDA ] [ KEGG ]   [ MEROPS ]
Domaine pattern : Prosite (Expaxy)FAT (PS51189)    FATC (PS51190)    HEAT_REPEAT (PS50077)    PI3_4_KINASE_2 (PS00916)    PI3_4_KINASE_3 (PS50290)   
Domains : Interpro (EBI)ARM-like    ARM-type_fold    FATC_dom    HEAT_type_2    Kinase-like_dom_sf    PI3/4_kinase_cat_dom    PI3/4_kinase_cat_sf    PI3/4_kinase_CS    PIK-rel_kinase_FAT    PIK_FAT    TPR-like_helical_dom_sf    UME   
Domain families : Pfam (Sanger)FAT (PF02259)    FATC (PF02260)    PI3_PI4_kinase (PF00454)    UME (PF08064)   
Domain families : Pfam (NCBI)pfam02259    pfam02260    pfam00454    pfam08064   
Domain families : Smart (EMBL)FATC (SM01343)  PI3Kc (SM00146)  UME (SM00802)  
Conserved Domain (NCBI)ATR
PDB Europe5YZ0   
PDB (PDBSum)5YZ0   
PDB (IMB)5YZ0   
Structural Biology KnowledgeBase5YZ0   
SCOP (Structural Classification of Proteins)5YZ0   
CATH (Classification of proteins structures)5YZ0   
AlphaFold pdb e-kbQ13535   
Human Protein Atlas [tissue]ENSG00000175054-ATR [tissue]
Protein Interaction databases
IntAct (EBI)Q13535
Complex Portal (EBI)Q13535 CPX-3622 ATR-ATRIP DNA damage-sensing kinase complex
Ontologies - Pathways
Ontology : AmiGODNA damage checkpoint signaling  DNA damage checkpoint signaling  telomere maintenance  chromosome, telomeric region  DNA binding  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  chromosome  Golgi apparatus  DNA replication  DNA repair  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  multicellular organism development  negative regulation of DNA replication  PML body  peptidyl-serine phosphorylation  replication fork processing  positive regulation of telomere maintenance via telomerase  MutLalpha complex binding  MutSalpha complex binding  cellular response to UV  interstrand cross-link repair  response to drug  positive regulation of DNA damage response, signal transduction by p53 class mediator  protein autophosphorylation  protein localization to chromosome, telomeric region  cellular response to gamma radiation  replicative senescence  establishment of RNA localization to telomere  establishment of protein-containing complex localization to telomere  protein serine kinase activity  protein threonine kinase activity  regulation of cellular response to heat  regulation of signal transduction by p53 class mediator  positive regulation of telomerase catalytic core complex assembly  
Ontology : EGO-EBIDNA damage checkpoint signaling  DNA damage checkpoint signaling  telomere maintenance  chromosome, telomeric region  DNA binding  protein kinase activity  protein serine/threonine kinase activity  protein serine/threonine kinase activity  protein binding  ATP binding  nucleus  nucleoplasm  nucleoplasm  chromosome  Golgi apparatus  DNA replication  DNA repair  cellular response to DNA damage stimulus  cellular response to DNA damage stimulus  multicellular organism development  negative regulation of DNA replication  PML body  peptidyl-serine phosphorylation  replication fork processing  positive regulation of telomere maintenance via telomerase  MutLalpha complex binding  MutSalpha complex binding  cellular response to UV  interstrand cross-link repair  response to drug  positive regulation of DNA damage response, signal transduction by p53 class mediator  protein autophosphorylation  protein localization to chromosome, telomeric region  cellular response to gamma radiation  replicative senescence  establishment of RNA localization to telomere  establishment of protein-containing complex localization to telomere  protein serine kinase activity  protein threonine kinase activity  regulation of cellular response to heat  regulation of signal transduction by p53 class mediator  positive regulation of telomerase catalytic core complex assembly  
Pathways : BIOCARTACell Cycle: G2/M Checkpoint [Genes]    Regulation of cell cycle progression by Plk3 [Genes]    Role of BRCA1, BRCA2 and ATR in Cancer Susceptibility [Genes]    Cell Cycle: G1/S Check Point [Genes]   
Pathways : KEGGFanconi anemia pathway    Cell cycle    p53 signaling pathway    HTLV-I infection   
REACTOMEQ13535 [protein]
REACTOME PathwaysR-HSA-69473 [pathway]   
NDEx NetworkATR
Atlas of Cancer Signalling NetworkATR
Wikipedia pathwaysATR
Orthology - Evolution
GeneTree (enSembl)ENSG00000175054
Phylogenetic Trees/Animal Genes : TreeFamATR
Homologs : HomoloGeneATR
Homology/Alignments : Family Browser (UCSC)ATR
Gene fusions - Rearrangements
Fusion : MitelmanADGRV1::ATR [5q14.3/3q23]  
Fusion : MitelmanATR::DBR1 [3q23/3q22.3]  
Fusion : MitelmanWWTR1::ATR [3q25.1/3q23]  
Fusion : QuiverATR
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerATR [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)ATR
Exome Variant ServerATR
GNOMAD BrowserENSG00000175054
Varsome BrowserATR
ACMGATR variants
Genomic Variants (DGV)ATR [DGVbeta]
DECIPHERATR [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisATR 
ICGC Data PortalATR 
TCGA Data PortalATR 
Broad Tumor PortalATR
OASIS PortalATR [ Somatic mutations - Copy number]
Cancer Gene: CensusATR 
Somatic Mutations in Cancer : COSMICATR  [overview]  [genome browser]  [tissue]  [distribution]  
Somatic Mutations in Cancer : COSMIC3DATR
Mutations and Diseases : HGMDATR
intOGen PortalATR
LOVD (Leiden Open Variation Database)[gene] [transcripts] [variants]
DgiDB (Drug Gene Interaction Database)ATR
DoCM (Curated mutations)ATR
CIViC (Clinical Interpretations of Variants in Cancer)ATR
NCG (London)ATR
Impact of mutations[PolyPhen2] [Provean] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
OMIM210600    601215    614564   
Orphanet954    21457   
Genetic Testing Registry ATR
NextProtQ13535 [Medical]
Target ValidationATR
Huge Navigator ATR [HugePedia]
Clinical trials, drugs, therapy
Protein Interactions : CTDATR
Pharm GKB GenePA74
Pharm GKB PathwaysPA166115250   
Clinical trialATR
DataMed IndexATR
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:12:57 CEST 2021

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