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Gene Review

ATR  -  ATR serine/threonine kinase

Homo sapiens

Synonyms: Ataxia telangiectasia and Rad3-related protein, FCTCS, FRAP-related protein 1, FRP1, MEC1, ...
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Disease relevance of ATR

  • While NBS shares overlapping characteristics with ataxia telangiectasia, it also has features overlapping with ATR-Seckel (ATR: ataxia-telangiectasia and Rad3-related protein) syndrome, a subclass of Seckel syndrome mutated in ATR [1].
  • We have uncovered novel phenotypes caused by MRN deficiency that support a functional link between this complex, ATR and Smc1, including hypersensitivity to UV exposure, a defective UV responsive intra-S phase checkpoint and a specific pattern of genomic instability [2].
  • In the present study, we demonstrate that HIV-1 infection of primary, human CD4(+) lymphocytes causes G(2) arrest in a Vpr-dependent manner and that this response requires ATR, as shown by RNA interference [3].
  • Here we show that infection with an adenovirus lacking the E4 region also induces a cellular DNA damage response, with activation of ATM and ATR [4].
  • Moreover, induction of ATR(ki) produced a 10-fold increase in chromosomal aberrations, further emphasizing the vital role for ATR in genetic stability [5].

Psychiatry related information on ATR


High impact information on ATR

  • Although it is known that MSCI and MSUC are both dependent on histone H2A.X phosphorylation mediated by the kinase ATR, and cause repressive H3 Lys9 dimethylation, the mechanisms underlying silencing are largely unidentified [7].
  • Paradoxically, telomere function depends on checkpoint proteins such as ATM and ATR, but a molecular model explaining this seemingly contradictory relationship has been missing so far [8].
  • They report that a physical interaction between ATR and a distinct domain of TopBP1 greatly enhances ATR kinase activity [9].
  • The nuclear protein kinase ATR is a key regulator of genome integrity that functions at checkpoints for damaged or incompletely replicated DNA [9].
  • First, the ATR-dependent machinery is recruited to telomeres before telomere replication is completed, likely in response to single-stranded DNA resulting from replication fork stalling [8].

Chemical compound and disease context of ATR

  • Taken together, these data suggest that the effect(s) of caffeine on HIV-1 transduction is mediated at least partly by the inhibition of the ATR pathway but is not dependent on the caffeine-mediated inhibition of cell cycle checkpoints [10].

Biological context of ATR

  • These findings demonstrate that ATR/ATM-dependent phosphorylation of hRad17 is a critical early event during checkpoint signalling in DNA-damaged cells [11].
  • The dramatic relocalization of ATR in response to DNA damage points to a possible mechanism for its ability to enhance the phosphorylation of substrates in response to DNA damage [12].
  • Thus, MCPH1 also has an ATR-independent role in maintaining inhibitory Cdk1 phosphorylation, which prevents premature entry into mitosis [13].
  • These results suggest that tCdc6 proteins act as dominant-negative inhibitors of replication initiation and that they disrupt chromatin structure and/or induce DNA damage, leading to the activation of ATM/ATR kinase activation and p53-Bax-mediated apoptosis [14].
  • MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation [15].

Anatomical context of ATR


Associations of ATR with chemical compounds

  • They are also impaired in ubiquitination of FANCD2 after HU treatment, which is ATR dependent [1].
  • These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG [15].
  • Here, we show that thymidine, which slows the progression of replication forks by depleting cellular pools of dCTP, induces a novel DNA damage response that, uniquely, depends on both ATM and ATR [18].
  • Together, these results suggest a relationship between BLM, ATR, and the RMN complex in the response to replication arrest, proposing a role for BLM protein and RMN complex in the resolution of stalled replication forks [19].
  • Expression of a kinase-inactive allele of ATR (ATRkd) in human fibroblasts causes increased sensitivity to ionizing radiation (IR), cis-platinum and methyl methanesulfonate, but only slight UV radiation sensitivity [20].

Physical interactions of ATR

  • These results demonstrate that the Mre11 complex can function as a damage sensor upstream of ATM/ATR signaling in mammalian cells [4].
  • PP5 forms a complex with ATR in a genotoxic stress-inducible manner [21].
  • ATR couples FANCD2 monoubiquitination to the DNA-damage response [22].
  • In response to hydroxyurea, UV or aphidicolin, Claspin is phosphorylated in the Chk1-binding domain and its protein levels are increased in an ATR-dependent manner [23].

Enzymatic interactions of ATR

  • ATR phosphorylates BRCA1 on six Ser/Thr residues, including Ser 1423, in vitro [12].
  • Rad17 binds to chromatin prior to damage and is phosphorylated by ATR on chromatin after damage but Rad17's phosphorylation is not required for Rad9 loading onto chromatin [24].
  • Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage [25].
  • While ATR phosphorylates the N-terminus of RPA70, Chk1 preferentially phosphorylates RPA's major ssDNA binding domain [26].
  • In response to genotoxic stress, Chk1 is phosphorylated on serines 317 (S317) and 345 (S345) by the ataxia-telangiectasia-related (ATR) protein kinase [27].
  • Nbs1 is phosphorylated by ATR at Ser-343 when replication forks are stalled, and this phosphorylation event is also important for down-regulating DNA replication following UV treatment [28].

Co-localisations of ATR


Regulatory relationships of ATR

  • ATM regulates ATR chromatin loading in response to DNA double-strand breaks [30].
  • Moreover, overexpression of kinase-inactive ATR in U2OS cells severely attenuated UVC-induced Chk1 phosphorylation and reversed the UVC-induced inhibition of replicon initiation, as did overexpression of kinase-inactive Chk1 [16].
  • ATR knock-down with siRNA suppressed CPT-induced RPA2 hyperphosphorylation and focus formation [31].
  • In response to DNA damage, ATM/ATR-dependent checkpoint pathways inhibit Plk1 activity [32].
  • Furthermore, Xenopus egg extracts containing a version of TopBP1 with an inactivating point mutation in the ATR-activating domain are defective in checkpoint regulation [33].
  • Our results suggest that HCLK2 functions in the same pathway as TopBP1 but that the two proteins regulate different steps in ATR activation [34].

Other interactions of ATR

  • Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress [12].
  • We show that Nbs1 also facilitates ATR-dependent phosphorylation [1].
  • These observations rule out ATR and implicate both ATM and DNA-PK in RPA2 phosphorylation after exposure to IR [35].
  • Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4 [36].
  • However, activation of the G2/M checkpoint in response to IR escapes this accepted paradigm because it is dependent on both ATM and ATR but independent of Chk2 [30].
  • Cellular complementation experiments demonstrate that TopBP1-mediated ATR activation is required for checkpoint signaling and cellular viability [37].

Analytical, diagnostic and therapeutic context of ATR


  1. Nbs1 is required for ATR-dependent phosphorylation events. Stiff, T., Reis, C., Alderton, G.K., Woodbine, L., O'Driscoll, M., Jeggo, P.A. EMBO J. (2005) [Pubmed]
  2. Rad50 depletion impacts upon ATR-dependent DNA damage responses. Zhong, H., Bryson, A., Eckersdorff, M., Ferguson, D.O. Hum. Mol. Genet. (2005) [Pubmed]
  3. Human immunodeficiency virus type 1 vpr induces DNA replication stress in vitro and in vivo. Zimmerman, E.S., Sherman, M.P., Blackett, J.L., Neidleman, J.A., Kreis, C., Mundt, P., Williams, S.A., Warmerdam, M., Kahn, J., Hecht, F.M., Grant, R.M., de Noronha, C.M., Weyrich, A.S., Greene, W.C., Planelles, V. J. Virol. (2006) [Pubmed]
  4. The Mre11 complex is required for ATM activation and the G2/M checkpoint. Carson, C.T., Schwartz, R.A., Stracker, T.H., Lilley, C.E., Lee, D.V., Weitzman, M.D. EMBO J. (2003) [Pubmed]
  5. The human decatenation checkpoint. Deming, P.B., Cistulli, C.A., Zhao, H., Graves, P.R., Piwnica-Worms, H., Paules, R.S., Downes, C.S., Kaufmann, W.K. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. Chromosomal instability at common fragile sites in Seckel syndrome. Casper, A.M., Durkin, S.G., Arlt, M.F., Glover, T.W. Am. J. Hum. Genet. (2004) [Pubmed]
  7. Chromosome-wide nucleosome replacement and H3.3 incorporation during mammalian meiotic sex chromosome inactivation. van der Heijden, G.W., Derijck, A.A., Pósfai, E., Giele, M., Pelczar, P., Ramos, L., Wansink, D.G., van der Vlag, J., Peters, A.H., de Boer, P. Nat. Genet. (2007) [Pubmed]
  8. The DNA damage machinery and homologous recombination pathway act consecutively to protect human telomeres. Verdun, R.E., Karlseder, J. Cell (2006) [Pubmed]
  9. TOPping up ATR activity. Bartek, J., Mailand, N. Cell (2006) [Pubmed]
  10. Caffeine inhibits human immunodeficiency virus type 1 transduction of nondividing cells. Daniel, R., Marusich, E., Argyris, E., Zhao, R.Y., Skalka, A.M., Pomerantz, R.J. J. Virol. (2005) [Pubmed]
  11. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Bao, S., Tibbetts, R.S., Brumbaugh, K.M., Fang, Y., Richardson, D.A., Ali, A., Chen, S.M., Abraham, R.T., Wang, X.F. Nature (2001) [Pubmed]
  12. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Tibbetts, R.S., Cortez, D., Brumbaugh, K.M., Scully, R., Livingston, D., Elledge, S.J., Abraham, R.T. Genes Dev. (2000) [Pubmed]
  13. Regulation of mitotic entry by microcephalin and its overlap with ATR signalling. Alderton, G.K., Galbiati, L., Griffith, E., Surinya, K.H., Neitzel, H., Jackson, A.P., Jeggo, P.A., O'Driscoll, M. Nat. Cell Biol. (2006) [Pubmed]
  14. Cleavage of Cdc6 by caspase-3 promotes ATM/ATR kinase-mediated apoptosis of HeLa cells. Yim, H., Hwang, I.S., Choi, J.S., Chun, K.H., Jin, Y.H., Ham, Y.M., Lee, K.Y., Lee, S.K. J. Cell Biol. (2006) [Pubmed]
  15. 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) [Pubmed]
  16. An ATR- and Chk1-dependent S checkpoint inhibits replicon initiation following UVC-induced DNA damage. Heffernan, T.P., Simpson, D.A., Frank, A.R., Heinloth, A.N., Paules, R.S., Cordeiro-Stone, M., Kaufmann, W.K. Mol. Cell. Biol. (2002) [Pubmed]
  17. cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Cimprich, K.A., Shin, T.B., Keith, C.T., Schreiber, S.L. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  18. ATM is required for the cellular response to thymidine induced replication fork stress. Bolderson, E., Scorah, J., Helleday, T., Smythe, C., Meuth, M. Hum. Mol. Genet. (2004) [Pubmed]
  19. Bloom's syndrome protein is required for correct relocalization of RAD50/MRE11/NBS1 complex after replication fork arrest. Franchitto, A., Pichierri, P. J. Cell Biol. (2002) [Pubmed]
  20. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. Cliby, W.A., Roberts, C.J., Cimprich, K.A., Stringer, C.M., Lamb, J.R., Schreiber, S.L., Friend, S.H. EMBO J. (1998) [Pubmed]
  21. Protein phosphatase 5 is required for ATR-mediated checkpoint activation. Zhang, J., Bao, S., Furumai, R., Kucera, K.S., Ali, A., Dean, N.M., Wang, X.F. Mol. Cell. Biol. (2005) [Pubmed]
  22. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Andreassen, P.R., D'Andrea, A.D., Taniguchi, T. Genes Dev. (2004) [Pubmed]
  23. Regulation of Claspin degradation by the ubiquitin-proteosome pathway during the cell cycle and in response to ATR-dependent checkpoint activation. Bennett, L.N., Clarke, P.R. FEBS Lett. (2006) [Pubmed]
  24. Regulation of ATR substrate selection by Rad17-dependent loading of Rad9 complexes onto chromatin. Zou, L., Cortez, D., Elledge, S.J. Genes Dev. (2002) [Pubmed]
  25. Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle. Pichierri, P., Rosselli, F., Franchitto, A. Oncogene (2003) [Pubmed]
  26. Phosphorylation of replication protein A by S-phase checkpoint kinases. Liu, J.S., Kuo, S.R., Melendy, T. DNA Repair (Amst.) (2006) [Pubmed]
  27. Phosphorylation of Chk1 by ATR Is Antagonized by a Chk1-Regulated Protein Phosphatase 2A Circuit. Leung-Pineda, V., Ryan, C.E., Piwnica-Worms, H. Mol. Cell. Biol. (2006) [Pubmed]
  28. The Mre11-Rad50-Nbs1 complex acts both upstream and downstream of ataxia telangiectasia mutated and Rad3-related protein (ATR) to regulate the S-phase checkpoint following UV treatment. Olson, E., Nievera, C.J., Lee, A.Y., Chen, L., Wu, X. J. Biol. Chem. (2007) [Pubmed]
  29. Claspin operates downstream of TopBP1 to direct ATR signaling towards Chk1 activation. Liu, S., Bekker-Jensen, S., Mailand, N., Lukas, C., Bartek, J., Lukas, J. Mol. Cell. Biol. (2006) [Pubmed]
  30. ATM regulates ATR chromatin loading in response to DNA double-strand breaks. Cuadrado, M., Martinez-Pastor, B., Murga, M., Toledo, L.I., Gutierrez-Martinez, P., Lopez, E., Fernandez-Capetillo, O. J. Exp. Med. (2006) [Pubmed]
  31. Differential involvement of phosphatidylinositol 3-kinase-related protein kinases in hyperphosphorylation of replication protein A2 in response to replication-mediated DNA double-strand breaks. Sakasai, R., Shinohe, K., Ichijima, Y., Okita, N., Shibata, A., Asahina, K., Teraoka, H. Genes Cells (2006) [Pubmed]
  32. Phosphorylation of Plk1 at S137 and T210 is inhibited in response to DNA damage. Tsvetkov, L., Stern, D.F. Cell Cycle (2005) [Pubmed]
  33. TopBP1 activates the ATR-ATRIP complex. Kumagai, A., Lee, J., Yoo, H.Y., Dunphy, W.G. Cell (2006) [Pubmed]
  34. HCLK2 is required for activity of the DNA damage response kinase ATR. Rendtlew Danielsen, J.M., Larsen, D.H., Schou, K.B., Freire, R., Falck, J., Bartek, J., Lukas, J. J. Biol. Chem. (2009) [Pubmed]
  35. Replication protein A2 phosphorylation after DNA damage by the coordinated action of ataxia telangiectasia-mutated and DNA-dependent protein kinase. Wang, H., Guan, J., Wang, H., Perrault, A.R., Wang, Y., Iliakis, G. Cancer Res. (2001) [Pubmed]
  36. Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4. Schmidt, D.R., Schreiber, S.L. Biochemistry (1999) [Pubmed]
  37. TopBP1 activates ATR through ATRIP and a PIKK regulatory domain. Mordes, D.A., Glick, G.G., Zhao, R., Cortez, D. Genes Dev. (2008) [Pubmed]
  38. ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background. Fang, Y., Tsao, C.C., Goodman, B.K., Furumai, R., Tirado, C.A., Abraham, R.T., Wang, X.F. EMBO J. (2004) [Pubmed]
  39. ATR-mediated checkpoint pathways regulate phosphorylation and activation of human Chk1. Zhao, H., Piwnica-Worms, H. Mol. Cell. Biol. (2001) [Pubmed]
  40. Preferential binding of ATR protein to UV-damaged DNA. Unsal-Kaçmaz, K., Makhov, A.M., Griffith, J.D., Sancar, A. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
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