Ataxia telangiectasia and Rad3 related

Ataxia telangiectasia and Rad3 related
Identifiers
Symbols	ATR; FRP1; MEC1; SCKL; SCKL1
External IDs	OMIM: 601215 HomoloGene: 96916 GeneCards: ATR Gene
EC number	2.7.11.1
Gene Ontology Molecular function • nucleotide binding • DNA binding • protein kinase activity • protein serine/threonine kinase activity • protein serine/threonine kinase activity • protein binding • ATP binding • MutLalpha complex binding • MutSalpha complex binding Cellular component • XY body • nucleus • nucleoplasm • nucleoplasm • PML body Biological process • cell cycle checkpoint • DNA damage checkpoint • DNA replication • DNA repair • protein phosphorylation • response to DNA damage stimulus • cell cycle • multicellular organismal development • negative regulation of DNA replication • peptidyl-serine phosphorylation • cellular response to UV • regulation of protein binding • positive regulation of DNA damage response, signal transduction by p53 class mediator • protein autophosphorylation • cellular response to gamma radiation • replicative senescence Sources: Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	545	n/a
Ensembl	ENSG00000175054	n/a
UniProt	Q13535	n/a
RefSeq (mRNA)	NM_001184.3	n/a
RefSeq (protein)	NP_001175.2	n/a
Location (UCSC)	Chr 3: 142.17 – 142.3 Mb	n/a
PubMed search	[1]	n/a

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.

Function

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

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]

Interactions

Ataxia telangiectasia and Rad3 related has been shown to interact with RAD17,^[8][9] Histone deacetylase 2,^[10] MSH2,^[11] CHD4,^[10] BRCA1,^{[12][8][13][14]} P53^[15][8] and RHEB.^[16]

References

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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=39722. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=452488. 
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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=196009. 
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. ^ ^{a b c} Kim, S T; Lim D S, Canman C E, Kastan M B (Dec. 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. (UNITED STATES) 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. ISSN 0021-9258. PMID 10608806. 
9. ^ Bao, S; Tibbetts R S, Brumbaugh K M, Fang Y, Richardson D A, Ali A, Chen S M, Abraham R T, Wang X F (Jun. 2001). "ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses". Nature (England) 411 (6840): 969–74. doi:10.1038/35082110. ISSN 0028-0836. PMID 11418864. 
10. ^ ^{a b} Schmidt, D R; Schreiber S L (Nov. 1999). "Molecular association between ATR and two components of the nucleosome remodeling and deacetylating complex, HDAC2 and CHD4". Biochemistry (UNITED STATES) 38 (44): 14711–7. doi:10.1021/bi991614n. ISSN 0006-2960. PMID 10545197. 
11. ^ Wang, Yi; Qin Jun (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. (United States) 100 (26): 15387–92. doi:10.1073/pnas.2536810100. ISSN 0027-8424. PMC 307577. PMID 14657349. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=307577. 
12. ^ Tibbetts, R S; Cortez D, Brumbaugh K M, Scully R, Livingston D, Elledge S J, Abraham R T (Dec. 2000). "Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress". Genes Dev. (UNITED STATES) 14 (23): 2989–3002. doi:10.1101/gad.851000. ISSN 0890-9369. PMC 317107. PMID 11114888. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=317107. 
13. ^ Chen, J (Sep. 2000). "Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage". Cancer Res. (UNITED STATES) 60 (18): 5037–9. ISSN 0008-5472. PMID 11016625. 
14. ^ Gatei, M; Zhou B B, Hobson K, Scott S, Young D, Khanna K K (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. (United States) 276 (20): 17276–80. doi:10.1074/jbc.M011681200. ISSN 0021-9258. PMID 11278964. 
15. ^ Fabbro, Megan; Savage Kienan, Hobson Karen, Deans Andrew J, Powell Simon N, McArthur Grant A, Khanna Kum Kum (Jul. 2004). "BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage". J. Biol. Chem. (United States) 279 (30): 31251–8. doi:10.1074/jbc.M405372200. ISSN 0021-9258. PMID 15159397. 
16. ^ Long, Xiaomeng; Lin Yenshou, Ortiz-Vega Sara, Yonezawa Kazuyoshi, Avruch Joseph (Apr. 2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. (England) 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. ISSN 0960-9822. PMID 15854902. 

Further reading

• Giaccia AJ, Kastan MB (1998). "The complexity of p53 modulation: emerging patterns from divergent signals.". Genes Dev. 12 (19): 2973–83. doi:10.1101/gad.12.19.2973. PMID 9765199. 
• Shiloh Y (2001). "ATM and ATR: networking cellular responses to DNA damage.". Curr. Opin. Genet. Dev. 11 (1): 71–7. doi:10.1016/S0959-437X(00)00159-3. PMID 11163154. 
• Kastan MB, Lim DS (2001). "The many substrates and functions of ATM.". Nat. Rev. Mol. Cell Biol. 1 (3): 179–86. doi:10.1038/35043058. PMID 11252893. 
• Abraham RT (2005). "The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways.". DNA Repair (Amst.) 3 (8-9): 919–25. doi:10.1016/j.dnarep.2004.04.003. PMID 15279777. 
• Li L, Li HS, Pauza CD, et al. (2006). "Roles of HIV-1 auxiliary proteins in viral pathogenesis and host-pathogen interactions.". Cell Res. 15 (11-12): 923–34. doi:10.1038/sj.cr.7290370. PMID 16354571. 

External links

• Drosophila meiotic-41 - The Interactive Fly

Serine/threonine-specific protein kinases (EC 2.7.11.21-EC 2.7.11.30)
Polo kinase (EC 2.7.11.21) PLK1, PLK2, PLK3, PLK4 Cyclin-dependent kinase (EC 2.7.11.22) CDK1, CDK2, CDKL2, CDK3, CDK4, CDK5, CDKL5, CDK6, CDK7, CDK8, CDK9, CDK10, CDC2L5, CRKRS, PCTK1, PCTK2, PCTK3, PFTK1, CDC2L1 (RNA-polymerase)-subunit kinase (EC 2.7.11.23) RPS6KA5, RPS6KA4, P70S6 kinase, P70-S6 Kinase 1, RPS6KB2, RPS6KA2, RPS6KA3, RPS6KA1, RPS6KC1 Mitogen-activated protein kinase (EC 2.7.11.24) Extracellular signal-regulated (MAPK1, MAPK3, MAPK4, MAPK6, MAPK7, MAPK12, MAPK15), C-Jun N-terminal (MAPK8, MAPK9, MAPK10), P38 mitogen-activated protein (MAPK11, MAPK13, MAPK14) MAP3K (EC 2.7.11.25) MAP kinase kinase kinases (MAP3K1, MAP3K2, MAP3K3, MAP3K4, MAP3K5, MAP3K6, MAP3K7, MAP3K8) RAFs (ARAF, BRAF, KSR1, KSR2), MLKs (MAP3K12, MAP3K13, MAP3K9, MAP3K10, MAP3K11, MAP3K7, ZAK), CDC7, MAP3K14 Tau-protein kinase (EC 2.7.11.26) TPK1, TTK, GSK-3 (acetyl-CoA carboxylase) kinase (EC 2.7.11.27) - Tropomyosin kinase (EC 2.7.11.28) - Low-density-lipoprotein receptor kinase (EC 2.7.11.29) - Receptor protein serine/threonine kinase (EC 2.7.11.30) Bone morphogenetic protein receptors (BMPR1, BMPR1A, BMPR1B, BMPR2), ACVR1, ACVR1B, ACVR1C, ACVR2A, ACVR2B, ACVRL1, Anti-Müllerian hormone receptor

Dual-specificity kinases (EC 2.7.12)
MAP2K MAP2K1, MAP2K2, MAP2K3, MAP2K4, MAP2K5, MAP2K6, MAP2K7

B enzm: 1.1/2/3/4/5/6/7/8/10/11/13/14/15-18, 2.1/2/3/4/5/6/7/8, 2.7.10, 2.7.11-12, 3.1/2/3/4/5/6/7, 3.1.3.48, 3.4.21/22/23/24, 4.1/2/3/4/5/6, 5.1/2/3/4/99, 6.1-3/4/5-6