| 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]
Publication Abstract from PubMed
In response to DNA damage or replication fork stalling, the basal activity of Mec1(ATR) is stimulated in a cell-cycle-dependent manner, leading to cell-cycle arrest and the promotion of DNA repair. Mec1(ATR) dysfunction leads to cell death in yeast and causes chromosome instability and embryonic lethality in mammals. Thus, ATR is a major target for cancer therapies in homologous recombination-deficient cancers. Here we identify a single mutation in Mec1, conserved in ATR, that results in constitutive activity. Using cryo-electron microscopy, we determine the structures of this constitutively active form (Mec1(F2244L)-Ddc2) at 2.8 A and the wild type at 3.8 A, both in complex with Mg(2+)-AMP-PNP. These structures yield a near-complete atomic model for Mec1-Ddc2 and uncover the molecular basis for low basal activity and the conformational changes required for activation. Combined with biochemical and genetic data, we discover key regulatory regions and propose a Mec1 activation mechanism.
Mechanism of auto-inhibition and activation of Mec1(ATR) checkpoint kinase.,Tannous EA, Yates LA, Zhang X, Burgers PM Nat Struct Mol Biol. 2021 Jan;28(1):50-61. doi: 10.1038/s41594-020-00522-0. Epub , 2020 Nov 9. PMID:33169019[13]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Tannous EA, Yates LA, Zhang X, Burgers PM. Mechanism of auto-inhibition and activation of Mec1(ATR) checkpoint kinase. Nat Struct Mol Biol. 2021 Jan;28(1):50-61. PMID:33169019 doi:10.1038/s41594-020-00522-0
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