| Structural highlights
Disease
[ATR_HUMAN] Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome;Seckel syndrome. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. [ATRIP_HUMAN] Seckel syndrome.
Function
[ATR_HUMAN] 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 p53/TP53, 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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [ATRIP_HUMAN] Required for checkpoint signaling after DNA damage. Required for ATR expression, possibly by stabilizing the protein.[25]
Publication Abstract from PubMed
ATR (ataxia telangiectasia-mutated and Rad3-related) protein kinase and ATRIP (ATR-interacting protein) form a complex and play a critical role in response to replication stress and DNA damage. Here, we determined the cryo-electron microscopy (EM) structure of the human ATR-ATRIP complex at 4.7 A resolution and built an atomic model of the C-terminal catalytic core of ATR (residues 1 521-2 644) at 3.9 A resolution. The complex adopts a hollow "heart" shape, consisting of two ATR monomers in distinct conformations. The EM map for ATRIP reveals 14 HEAT repeats in an extended "S" shape. The conformational flexibility of ATR allows ATRIP to properly lock the N-termini of the two ATR monomers to favor ATR-ATRIP complex formation and functional diversity. The isolated "head-head" and "tail-tail" each adopts a pseudo 2-fold symmetry. The catalytic pockets face outward and substrate access is not restricted by inhibitory elements. Our studies provide a structural basis for understanding the assembly of the ATR-ATRIP complex and a framework for characterizing ATR-mediated DNA repair pathways.Cell Research advance online publication 22 December 2017; doi:10.1038/cr.2017.158.
Cryo-EM structure of human ATR-ATRIP complex.,Rao Q, Liu M, Tian Y, Wu Z, Hao Y, Song L, Qin Z, Ding C, Wang HW, Wang J, Xu Y Cell Res. 2017 Dec 22. pii: cr2017158. doi: 10.1038/cr.2017.158. PMID:29271416[26]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Hall-Jackson CA, Cross DA, Morrice N, Smythe C. ATR is a caffeine-sensitive, DNA-activated protein kinase with a substrate specificity distinct from DNA-PK. Oncogene. 1999 Nov 18;18(48):6707-13. PMID:10597277 doi:http://dx.doi.org/10.1038/sj.onc.1203077
- ↑ Kim ST, Lim DS, Canman CE, Kastan MB. Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem. 1999 Dec 31;274(53):37538-43. PMID:10608806
- ↑ 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. Chk1 is an essential kinase that is regulated by Atr and required for the G(2)/M DNA damage checkpoint. Genes Dev. 2000 Jun 15;14(12):1448-59. PMID:10859164
- ↑ Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ, Abraham RT. Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress. Genes Dev. 2000 Dec 1;14(23):2989-3002. PMID:11114888
- ↑ Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A, Chen SM, Abraham RT, Wang XF. ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses. Nature. 2001 Jun 21;411(6840):969-74. PMID:11418864 doi:http://dx.doi.org/10.1038/35082110
- ↑ Ward IM, Chen J. Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem. 2001 Dec 21;276(51):47759-62. doi: 10.1074/jbc.C100569200. Epub 2001, Oct 22. PMID:11673449 doi:http://dx.doi.org/10.1074/jbc.C100569200
- ↑ Cortez D, Guntuku S, Qin J, Elledge SJ. ATR and ATRIP: partners in checkpoint signaling. Science. 2001 Nov 23;294(5547):1713-6. PMID:11721054 doi:http://dx.doi.org/10.1126/science.1065521
- ↑ Hammond EM, Denko NC, Dorie MJ, Abraham RT, Giaccia AJ. Hypoxia links ATR and p53 through replication arrest. Mol Cell Biol. 2002 Mar;22(6):1834-43. PMID:11865061
- ↑ Casper AM, Nghiem P, Arlt MF, Glover TW. ATR regulates fragile site stability. Cell. 2002 Dec 13;111(6):779-89. PMID:12526805
- ↑ Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003 Jun 6;300(5625):1542-8. PMID:12791985 doi:http://dx.doi.org/10.1126/science.1083430
- ↑ Barr SM, Leung CG, Chang EE, Cimprich KA. ATR kinase activity regulates the intranuclear translocation of ATR and RPA following ionizing radiation. Curr Biol. 2003 Jun 17;13(12):1047-51. PMID:12814551
- ↑ Wang Y, Qin J. 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. 2003 Dec 23;100(26):15387-92. Epub 2003 Dec 3. PMID:14657349 doi:http://dx.doi.org/10.1073/pnas.2536810100
- ↑ Unsal-Kacmaz K, Sancar A. Quaternary structure of ATR and effects of ATRIP and replication protein A on its DNA binding and kinase activities. Mol Cell Biol. 2004 Feb;24(3):1292-300. PMID:14729973
- ↑ Ward IM, Minn K, Chen J. UV-induced ataxia-telangiectasia-mutated and Rad3-related (ATR) activation requires replication stress. J Biol Chem. 2004 Mar 12;279(11):9677-80. Epub 2004 Jan 23. PMID:14742437 doi:http://dx.doi.org/10.1074/jbc.C300554200
- ↑ Cortez D, Glick G, Elledge SJ. Minichromosome maintenance proteins are direct targets of the ATM and ATR checkpoint kinases. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10078-83. doi:, 10.1073/pnas.0403410101. Epub 2004 Jun 21. PMID:15210935 doi:http://dx.doi.org/10.1073/pnas.0403410101
- ↑ Andreassen PR, D'Andrea AD, Taniguchi T. ATR couples FANCD2 monoubiquitination to the DNA-damage response. Genes Dev. 2004 Aug 15;18(16):1958-63. PMID:15314022 doi:http://dx.doi.org/10.1101/gad.1196104
- ↑ Alderton GK, Joenje H, Varon R, Borglum AD, Jeggo PA, O'Driscoll M. Seckel syndrome exhibits cellular features demonstrating defects in the ATR-signalling pathway. Hum Mol Genet. 2004 Dec 15;13(24):3127-38. Epub 2004 Oct 20. PMID:15496423 doi:http://dx.doi.org/ddh335
- ↑ Zhang J, Bao S, Furumai R, Kucera KS, Ali A, Dean NM, Wang XF. Protein phosphatase 5 is required for ATR-mediated checkpoint activation. Mol Cell Biol. 2005 Nov;25(22):9910-9. doi: 10.1128/MCB.25.22.9910-9919.2005. PMID:16260606 doi:http://dx.doi.org/10.1128/MCB.25.22.9910-9919.2005
- ↑ Kang Y, Cheong HM, Lee JH, Song PI, Lee KH, Kim SY, Jun JY, You HJ. Protein phosphatase 5 is necessary for ATR-mediated DNA repair. Biochem Biophys Res Commun. 2011 Jan 7;404(1):476-81. doi:, 10.1016/j.bbrc.2010.12.005. Epub 2010 Dec 6. PMID:21144835 doi:http://dx.doi.org/10.1016/j.bbrc.2010.12.005
- ↑ Haahr P, Hoffmann S, Tollenaere MA, Ho T, Toledo LI, Mann M, Bekker-Jensen S, Raschle M, Mailand N. Activation of the ATR kinase by the RPA-binding protein ETAA1. Nat Cell Biol. 2016 Nov;18(11):1196-1207. doi: 10.1038/ncb3422. Epub 2016 Oct 10. PMID:27723717 doi:http://dx.doi.org/10.1038/ncb3422
- ↑ Bass TE, Luzwick JW, Kavanaugh G, Carroll C, Dungrawala H, Glick GG, Feldkamp MD, Putney R, Chazin WJ, Cortez D. ETAA1 acts at stalled replication forks to maintain genome integrity. Nat Cell Biol. 2016 Nov;18(11):1185-1195. doi: 10.1038/ncb3415. Epub 2016 Oct 10. PMID:27723720 doi:http://dx.doi.org/10.1038/ncb3415
- ↑ Cliby WA, Roberts CJ, Cimprich KA, Stringer CM, Lamb JR, Schreiber SL, Friend SH. Overexpression of a kinase-inactive ATR protein causes sensitivity to DNA-damaging agents and defects in cell cycle checkpoints. EMBO J. 1998 Jan 2;17(1):159-69. PMID:9427750 doi:http://dx.doi.org/10.1093/emboj/17.1.159
- ↑ Wright JA, Keegan KS, Herendeen DR, Bentley NJ, Carr AM, Hoekstra MF, Concannon P. Protein kinase mutants of human ATR increase sensitivity to UV and ionizing radiation and abrogate cell cycle checkpoint control. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7445-50. PMID:9636169
- ↑ Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999 Jan 15;13(2):152-7. PMID:9925639
- ↑ Zou L, Elledge SJ. Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes. Science. 2003 Jun 6;300(5625):1542-8. PMID:12791985 doi:http://dx.doi.org/10.1126/science.1083430
- ↑ Rao Q, Liu M, Tian Y, Wu Z, Hao Y, Song L, Qin Z, Ding C, Wang HW, Wang J, Xu Y. Cryo-EM structure of human ATR-ATRIP complex. Cell Res. 2017 Dec 22. pii: cr2017158. doi: 10.1038/cr.2017.158. PMID:29271416 doi:http://dx.doi.org/10.1038/cr.2017.158
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