| Structural highlightsFunctionATM_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 by the MRX-complex to sites of DNA lesions immediately after damage to initiate non-homologous end-joining (NHEJ). Subsequently displaced by the RPA complex in a reaction probably involving the SAE2 protein. Phosphorylates MRE11 and XRS2, 2 subunits of the MRX-complex. The phosphorylation of MRE11 is a feedback response from the checkpoint signaling pathway. Phosphorylates RAD9, CHK1 and RAD53, leading to the activation of the CHK1 and RAD23 kinases involved in the DNA damage response 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 involved in genome stability. Required for the control of telomere length and genome stability.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
Yeast Tel1 and its highly conserved human ortholog ataxia-telangiectasia mutated (ATM) are large protein kinases central to the maintenance of genome integrity. Mutations in ATM are found in ataxia-telangiectasia (A-T) patients and ATM is one of the most frequently mutated genes in many cancers. Using cryoelectron microscopy, we present the structure of Tel1 in a nucleotide-bound state. Our structure reveals molecular details of key residues surrounding the nucleotide binding site and provides a structural and molecular basis for its intrinsically low basal activity. We show that the catalytic residues are in a productive conformation for catalysis, but the phosphatidylinositol 3-kinase-related kinase (PIKK) regulatory domain insert restricts peptide substrate access and the N-lobe is in an open conformation, thus explaining the requirement for Tel1 activation. Structural comparisons with other PIKKs suggest a conserved and common allosteric activation mechanism. Our work also provides a structural rationale for many mutations found in A-T and cancer.
Cryo-EM Structure of Nucleotide-Bound Tel1(ATM) Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations.,Yates LA, Williams RM, Hailemariam S, Ayala R, Burgers P, Zhang X Structure. 2019 Nov 4. pii: S0969-2126(19)30353-3. doi:, 10.1016/j.str.2019.10.012. PMID:31740029[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See AlsoReferences
- ↑ 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
- ↑ Myung K, Datta A, Kolodner RD. Suppression of spontaneous chromosomal rearrangements by S phase checkpoint functions in Saccharomyces cerevisiae. Cell. 2001 Feb 9;104(3):397-408. PMID:11239397
- ↑ Usui T, Ogawa H, Petrini JH. A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell. 2001 Jun;7(6):1255-66. PMID:11430828
- ↑ D'Amours D, Jackson SP. The yeast Xrs2 complex functions in S phase checkpoint regulation. Genes Dev. 2001 Sep 1;15(17):2238-49. PMID:11544181 doi:http://dx.doi.org/10.1101/gad.208701
- ↑ 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
- ↑ 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
- ↑ Nakada D, Matsumoto K, Sugimoto K. ATM-related Tel1 associates with double-strand breaks through an Xrs2-dependent mechanism. Genes Dev. 2003 Aug 15;17(16):1957-62. doi: 10.1101/gad.1099003. PMID:12923051 doi:http://dx.doi.org/10.1101/gad.1099003
- ↑ 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
- ↑ Chakhparonian M, Faucher D, Wellinger RJ. A mutation in yeast Tel1p that causes differential effects on the DNA damage checkpoint and telomere maintenance. Curr Genet. 2005 Nov;48(5):310-22. Epub 2005 Nov 4. PMID:16228207 doi:http://dx.doi.org/10.1007/s00294-005-0020-7
- ↑ Greenwell PW, Kronmal SL, Porter SE, Gassenhuber J, Obermaier B, Petes TD. TEL1, a gene involved in controlling telomere length in S. cerevisiae, is homologous to the human ataxia telangiectasia gene. Cell. 1995 Sep 8;82(5):823-9. PMID:7671310
- ↑ 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
- ↑ Yates LA, Williams RM, Hailemariam S, Ayala R, Burgers P, Zhang X. Cryo-EM Structure of Nucleotide-Bound Tel1(ATM) Unravels the Molecular Basis of Inhibition and Structural Rationale for Disease-Associated Mutations. Structure. 2019 Nov 4. pii: S0969-2126(19)30353-3. doi:, 10.1016/j.str.2019.10.012. PMID:31740029 doi:http://dx.doi.org/10.1016/j.str.2019.10.012
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