| Structural highlights
Function
[ATR_YEAST] 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. Recruited in complex with protein LCD1 by the single-strand-binding protein complex RPA to DNA lesions in order to initiate the DNA repair by homologous recombination, after the MRX-complex and TEL1 are displaced. Phosphorylates LCD1 and RPA2, a subunit of RPA, involved in DNA replication, repair and recombination. Phosphorylates RAD9, CHK1 and RAD53, which leads to the activation of the CHK1 and RAD53 kinases involved in DNA damage repair cascade. Phosphorylates histone H2A to form H2AS128ph (gamma-H2A) at sites of DNA damage, also involved in the regulation of DNA damage response mechanism. Phosphorylates also SLX4 and RTT107 which are proteins involved in genome stability. Required for cell growth and meiotic recombination.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [LCD1_YEAST] Forms a complex with the serine/threonine kinase MEC1 which activates checkpoint signaling upon genotoxic stresses. The MEC1-LCD1 complex is recruited by the single-strand-binding protein complex RPA to DNA lesions in order to initiate the DNA repair by homologous recombination, after the MRX-complex and TEL1 are displaced. Required for the recruitment of MEC1 to DNA lesions, the activation of CHK1 and RAD53 kinases and phosphorylation of RAD9 in response to DNA damage. Required for cell growth and meiotic recombination.[13] [14] [15] [16] [17] [18] [19] [20] [21]
Publication Abstract from PubMed
The ataxia telangiectasia-mutated and Rad3-related (ATR) kinase is a master regulator of DNA damage response and replication stress in humans, but the mechanism of its activation remains unclear. ATR acts together with its partner ATRIP. Using cryo-electron microscopy, we determined the structure of intact Mec1-Ddc2 (the yeast homolog of ATR-ATRIP), which is poised for catalysis, at a resolution of 3.9 angstroms. Mec1-Ddc2 forms a dimer of heterodimers through the PRD and FAT domains of Mec1 and the coiled-coil domain of Ddc2. The PRD and Bridge domains in Mec1 constitute critical regulatory sites. The activation loop of Mec1 is inhibited by the PRD, revealing an allosteric mechanism of kinase activation. Our study clarifies the architecture of ATR-ATRIP and provides a structural framework for the understanding of ATR regulation.
3.9 A structure of the yeast Mec1-Ddc2 complex, a homolog of human ATR-ATRIP.,Wang X, Ran T, Zhang X, Xin J, Zhang Z, Wu T, Wang W, Cai G Science. 2017 Dec 1;358(6367):1206-1209. doi: 10.1126/science.aan8414. PMID:29191911[22]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Mallory JC, Petes TD. Protein kinase activity of Tel1p and Mec1p, two Saccharomyces cerevisiae proteins related to the human ATM protein kinase. Proc Natl Acad Sci U S A. 2000 Dec 5;97(25):13749-54. doi:, 10.1073/pnas.250475697. PMID:11095737 doi:http://dx.doi.org/10.1073/pnas.250475697
- ↑ Downs JA, Lowndes NF, Jackson SP. A role for Saccharomyces cerevisiae histone H2A in DNA repair. Nature. 2000 Dec 21-28;408(6815):1001-4. PMID:11140636 doi:10.1038/35050000
- ↑ Paciotti V, Clerici M, Scotti M, Lucchini G, Longhese MP. Characterization of mec1 kinase-deficient mutants and of new hypomorphic mec1 alleles impairing subsets of the DNA damage response pathway. Mol Cell Biol. 2001 Jun;21(12):3913-25. PMID:11359899 doi:http://dx.doi.org/10.1128/MCB.21.12.3913-3925.2001
- ↑ Enomoto S, Glowczewski L, Berman J. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol Biol Cell. 2002 Aug;13(8):2626-38. PMID:12181334 doi:http://dx.doi.org/10.1091/mbc.02-02-0012
- ↑ Redon C, Pilch DR, Rogakou EP, Orr AH, Lowndes NF, Bonner WM. Yeast histone 2A serine 129 is essential for the efficient repair of checkpoint-blind DNA damage. EMBO Rep. 2003 Jul;4(7):678-84. PMID:12792653 doi:http://dx.doi.org/10.1038/sj.embor.embor871
- ↑ Lisby M, Barlow JH, Burgess RC, Rothstein R. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell. 2004 Sep 17;118(6):699-713. PMID:15369670 doi:http://dx.doi.org/10.1016/j.cell.2004.08.015
- ↑ Shroff R, Arbel-Eden A, Pilch D, Ira G, Bonner WM, Petrini JH, Haber JE, Lichten M. Distribution and dynamics of chromatin modification induced by a defined DNA double-strand break. Curr Biol. 2004 Oct 5;14(19):1703-11. PMID:15458641 doi:10.1016/j.cub.2004.09.047
- ↑ Flott S, Rouse J. Slx4 becomes phosphorylated after DNA damage in a Mec1/Tel1-dependent manner and is required for repair of DNA alkylation damage. Biochem J. 2005 Oct 15;391(Pt 2):325-33. PMID:15975089 doi:http://dx.doi.org/BJ20050768
- ↑ Nakada D, Hirano Y, Tanaka Y, Sugimoto K. Role of the C terminus of Mec1 checkpoint kinase in its localization to sites of DNA damage. Mol Biol Cell. 2005 Nov;16(11):5227-35. Epub 2005 Sep 7. PMID:16148046 doi:http://dx.doi.org/E05-05-0405
- ↑ Ma JL, Lee SJ, Duong JK, Stern DF. Activation of the checkpoint kinase Rad53 by the phosphatidyl inositol kinase-like kinase Mec1. J Biol Chem. 2006 Feb 17;281(7):3954-63. Epub 2005 Dec 19. PMID:16365046 doi:http://dx.doi.org/M507508200
- ↑ Kato R, Ogawa H. An essential gene, ESR1, is required for mitotic cell growth, DNA repair and meiotic recombination in Saccharomyces cerevisiae. Nucleic Acids Res. 1994 Aug 11;22(15):3104-12. PMID:8065923
- ↑ Sanchez Y, Desany BA, Jones WJ, Liu Q, Wang B, Elledge SJ. Regulation of RAD53 by the ATM-like kinases MEC1 and TEL1 in yeast cell cycle checkpoint pathways. Science. 1996 Jan 19;271(5247):357-60. PMID:8553072
- ↑ Paciotti V, Clerici M, Lucchini G, Longhese MP. The checkpoint protein Ddc2, functionally related to S. pombe Rad26, interacts with Mec1 and is regulated by Mec1-dependent phosphorylation in budding yeast. Genes Dev. 2000 Aug 15;14(16):2046-59. PMID:10950868
- ↑ Rouse J, Jackson SP. LCD1: an essential gene involved in checkpoint control and regulation of the MEC1 signalling pathway in Saccharomyces cerevisiae. EMBO J. 2000 Nov 1;19(21):5801-12. PMID:11060031 doi:http://dx.doi.org/10.1093/emboj/19.21.5801
- ↑ Wakayama T, Kondo T, Ando S, Matsumoto K, Sugimoto K. Pie1, a protein interacting with Mec1, controls cell growth and checkpoint responses in Saccharomyces cerevisiae. Mol Cell Biol. 2001 Feb;21(3):755-64. PMID:11154263 doi:http://dx.doi.org/10.1128/MCB.21.3.755-764.2001
- ↑ Clerici M, Paciotti V, Baldo V, Romano M, Lucchini G, Longhese MP. Hyperactivation of the yeast DNA damage checkpoint by TEL1 and DDC2 overexpression. EMBO J. 2001 Nov 15;20(22):6485-98. PMID:11707419 doi:http://dx.doi.org/10.1093/emboj/20.22.6485
- ↑ Rouse J, Jackson SP. Lcd1p recruits Mec1p to DNA lesions in vitro and in vivo. Mol Cell. 2002 Apr;9(4):857-69. PMID:11983176
- ↑ Enomoto S, Glowczewski L, Berman J. MEC3, MEC1, and DDC2 are essential components of a telomere checkpoint pathway required for cell cycle arrest during senescence in Saccharomyces cerevisiae. Mol Biol Cell. 2002 Aug;13(8):2626-38. PMID:12181334 doi:http://dx.doi.org/10.1091/mbc.02-02-0012
- ↑ Lisby M, Barlow JH, Burgess RC, Rothstein R. Choreography of the DNA damage response: spatiotemporal relationships among checkpoint and repair proteins. Cell. 2004 Sep 17;118(6):699-713. PMID:15369670 doi:http://dx.doi.org/10.1016/j.cell.2004.08.015
- ↑ Nakada D, Hirano Y, Tanaka Y, Sugimoto K. Role of the C terminus of Mec1 checkpoint kinase in its localization to sites of DNA damage. Mol Biol Cell. 2005 Nov;16(11):5227-35. Epub 2005 Sep 7. PMID:16148046 doi:http://dx.doi.org/E05-05-0405
- ↑ Ma JL, Lee SJ, Duong JK, Stern DF. Activation of the checkpoint kinase Rad53 by the phosphatidyl inositol kinase-like kinase Mec1. J Biol Chem. 2006 Feb 17;281(7):3954-63. Epub 2005 Dec 19. PMID:16365046 doi:http://dx.doi.org/M507508200
- ↑ Wang X, Ran T, Zhang X, Xin J, Zhang Z, Wu T, Wang W, Cai G. 3.9 A structure of the yeast Mec1-Ddc2 complex, a homolog of human ATR-ATRIP. Science. 2017 Dec 1;358(6367):1206-1209. doi: 10.1126/science.aan8414. PMID:29191911 doi:http://dx.doi.org/10.1126/science.aan8414
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