Ataxia telangiectasia and Rad3 related

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ATR serine/threonine kinase
External IDs OMIM601215 HomoloGene96916 IUPHAR: 1935 ChEMBL: 5024 GeneCards: ATR Gene
EC number
Species Human Mouse
Entrez 545 245000
Ensembl ENSG00000175054 ENSMUSG00000032409
UniProt Q13535 Q9JKK8
RefSeq (mRNA) NM_001184 NM_019864
RefSeq (protein) NP_001175 NP_063917
Location (UCSC) Chr 3:
142.17 – 142.3 Mb
Chr 9:
95.86 – 95.95 Mb
PubMed search [1] [2]

Serine/threonine-protein kinase ATR also known as ataxia telangiectasia and Rad3-related protein (ATR) or FRAP-related protein 1 (FRP1) is an enzyme that, in humans, is encoded by the ATR gene.[1][2] ATR belongs to the phosphatidylinositol 3-kinase-related kinase protein family.


ATR is a serine/threonine-specific protein kinase that is involved in sensing DNA damage and activating the DNA damage checkpoint, leading to cell cycle arrest.[3] ATR is activated in response to persistent single-stranded DNA, which is a common intermediate formed during DNA damage detection and repair. Single-stranded DNA occurs at stalled replication forks and as an intermediate in DNA repair pathways such as nucleotide excision repair and homologous recombination repair. ATR works with a partner protein called ATRIP to recognize single-stranded DNA coated with RPA.[4] Once ATR is activated, it phosphorylates Chk1, initiating a signal transduction cascade that culminates in cell cycle arrest. In addition to its role in activating the DNA damage checkpoint, ATR is thought to function in unperturbed DNA replication.[5]

ATR is related to a second checkpoint-activating kinase, ATM, which is activated by double strand breaks in DNA or chromatin disruption.[6]

Clinical significance[edit]

Mutations in ATR are responsible for Seckel syndrome, a rare human disorder that shares some characteristics with ataxia telangiectasia, which results from ATM mutation.[7]

ATR/ChK1 inhibitors can potentiate the effect of DNA cross-linking agents. The first clinical trials using inhibitors of ATR have been initiated by AstraZeneca, preferably in ATM-mutated chronic lymphocytic leukaemia (CLL), prolymphocytic leukaemia (PLL) or B-cell lymphoma patients and by Vertex Pharmaceuticals in advanced solid tumours.[8]


Ataxia telangiectasia and Rad3 related has been shown to interact with:


  1. ^ Cimprich KA, Shin TB, Keith CT, Schreiber SL (April 1996). "cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein". Proc. Natl. Acad. Sci. U.S.A. 93 (7): 2850–5. doi:10.1073/pnas.93.7.2850. PMC 39722. PMID 8610130. 
  2. ^ Bentley NJ, Holtzman DA, Flaggs G, Keegan KS, DeMaggio A, Ford JC, Hoekstra M, Carr AM (December 1996). "The Schizosaccharomyces pombe rad3 checkpoint gene". EMBO J. 15 (23): 6641–51. PMC 452488. PMID 8978690. 
  3. ^ Sancar A, Lindsey-Boltz LA, Unsal-Kaçmaz K, Linn S (2004). "Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints". Annu. Rev. Biochem. 73 (1): 39–85. doi:10.1146/annurev.biochem.73.011303.073723. PMID 15189136. 
  4. ^ Zou L, Elledge SJ (June 2003). "Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes". Science 300 (5625): 1542–8. doi:10.1126/science.1083430. PMID 12791985. 
  5. ^ Brown EJ, Baltimore D (March 2003). "Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance". Genes Dev. 17 (5): 615–28. doi:10.1101/gad.1067403. PMC 196009. PMID 12629044. 
  6. ^ Bakkenist CJ, Kastan MB (January 2003). "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation". Nature 421 (6922): 499–506. doi:10.1038/nature01368. PMID 12556884. 
  7. ^ O'Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (April 2003). "A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome". Nat. Genet. 33 (4): 497–501. doi:10.1038/ng1129. PMID 12640452. 
  8. ^ Llona-Minguez S, Höglund A, Jacques SA, Koolmeister T, Helleday T (May 2014). "Chemical strategies for development of ATR inhibitors". Expert Rev Mol Med. 16 (e10). doi:10.1017/erm.2014.10. PMID 24810715. 
  9. ^ a b c Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806. 
  10. ^ Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT (Dec 2000). "Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress". Genes Dev. 14 (23): 2989–3002. doi:10.1101/gad.851000. PMC 317107. PMID 11114888. 
  11. ^ Chen J (September 2000). "Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage". Cancer Res. 60 (18): 5037–9. PMID 11016625. 
  12. ^ Gatei M, Zhou BB, Hobson K, Scott S, Young D, Khanna KK (May 2001). "Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies". J. Biol. Chem. 276 (20): 17276–80. doi:10.1074/jbc.M011681200. PMID 11278964. 
  13. ^ a b Schmidt DR, Schreiber SL (November 1999). "Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4". Biochemistry 38 (44): 14711–7. doi:10.1021/bi991614n. PMID 10545197. 
  14. ^ Wang Y, Qin J (Dec 2003). "MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation". Proc. Natl. Acad. Sci. U.S.A. 100 (26): 15387–92. doi:10.1073/pnas.2536810100. PMC 307577. PMID 14657349. 
  15. ^ Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA, Khanna KK (July 2004). "BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage". J. Biol. Chem. 279 (30): 31251–8. doi:10.1074/jbc.M405372200. PMID 15159397. 
  16. ^ Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF (June 2001). "ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses". Nature 411 (6840): 969–74. doi:10.1038/35082110. PMID 11418864. 
  17. ^ Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (April 2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902. 

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