| Structural highlights
Disease
[ATM_HUMAN] Mantle cell lymphoma;B-cell chronic lymphocytic leukemia;Combined cervical dystonia;Ataxia-telangiectasia;Ataxia-telangiectasia variant. The disease is caused by mutations affecting the gene represented in this entry. Defects in ATM contribute to T-cell acute lymphoblastic leukemia (TALL) and T-prolymphocytic leukemia (TPLL). TPLL is characterized by a high white blood cell count, with a predominance of prolymphocytes, marked splenomegaly, lymphadenopathy, skin lesions and serous effusion. The clinical course is highly aggressive, with poor response to chemotherapy and short survival time. TPLL occurs both in adults as a sporadic disease and in younger AT patients.[1] [2] [3] [4] [5] Defects in ATM contribute to B-cell non-Hodgkin lymphomas (BNHL), including mantle cell lymphoma (MCL).[6] [7] [8] Defects in ATM contribute to B-cell chronic lymphocytic leukemia (BCLL). BCLL is the commonest form of leukemia in the elderly. It is characterized by the accumulation of mature CD5+ B-lymphocytes, lymphadenopathy, immunodeficiency and bone marrow failure.[9] [10] [11]
Function
[ATM_HUMAN] Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor. Recognizes the substrate consensus sequence [ST]-Q. Phosphorylates 'Ser-139' of histone variant H2AX/H2AFX at double strand breaks (DSBs), thereby regulating DNA damage response mechanism. Also plays a role in pre-B cell allelic exclusion, a process leading to expression of a single immunoglobulin heavy chain allele to enforce clonality and monospecific recognition by the B-cell antigen receptor (BCR) expressed on individual B-lymphocytes. After the introduction of DNA breaks by the RAG complex on one immunoglobulin allele, acts by mediating a repositioning of the second allele to pericentromeric heterochromatin, preventing accessibility to the RAG complex and recombination of the second allele. Also involved in signal transduction and cell cycle control. May function as a tumor suppressor. Necessary for activation of ABL1 and SAPK. Phosphorylates DYRK2, CHEK2, p53/TP53, FANCD2, NFKBIA, BRCA1, CTIP, nibrin (NBN), TERF1, RAD9 and DCLRE1C. May play a role in vesicle and/or protein transport. Could play a role in T-cell development, gonad and neurological function. Plays a role in replication-dependent histone mRNA degradation. Binds DNA ends. Phosphorylation of DYRK2 in nucleus in response to genotoxic stress prevents its MDM2-mediated ubiquitination and subsequent proteasome degradation. Phosphorylates ATF2 which stimulates its function in DNA damage response.[12] [13] [14] [15] [16] [17] [18] [19]
Publication Abstract from PubMed
Human checkpoint kinase ataxia telangiectasia-mutated (ATM) plays a key role in initiation of the DNA damage response following DNA double-strand breaks. ATM inhibition is a promising approach in cancer therapy, but, so far, detailed insights into the binding modes of known ATM inhibitors have been hampered due to the lack of high-resolution ATM structures. Using cryo-EM, we have determined the structure of human ATM to an overall resolution sufficient to build a near-complete atomic model and identify two hitherto unknown zinc-binding motifs. We determined the structure of the kinase domain bound to ATPgammaS and to the ATM inhibitors KU-55933 and M4076 at 2.8 A, 2.8 A and 3.0 A resolution, respectively. The mode of action and selectivity of the ATM inhibitors can be explained by structural comparison and provide a framework for structure-based drug design.
Molecular basis of human ATM kinase inhibition.,Stakyte K, Rotheneder M, Lammens K, Bartho JD, Gradler U, Fuchss T, Pehl U, Alt A, van de Logt E, Hopfner KP Nat Struct Mol Biol. 2021 Sep 23. pii: 10.1038/s41594-021-00654-x. doi:, 10.1038/s41594-021-00654-x. PMID:34556870[20]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Vorechovsky I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarstrom L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet. 1997 Sep;17(1):96-9. PMID:9288106 doi:https://dx.doi.org/10.1038/ng0997-96
- ↑ Stilgenbauer S, Schaffner C, Litterst A, Liebisch P, Gilad S, Bar-Shira A, James MR, Lichter P, Dohner H. Biallelic mutations in the ATM gene in T-prolymphocytic leukemia. Nat Med. 1997 Oct;3(10):1155-9. PMID:9334731
- ↑ Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor AM. ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer. Am J Hum Genet. 1998 Feb;62(2):334-45. PMID:9463314 doi:https://dx.doi.org/10.1086/301706
- ↑ Yuille MA, Coignet LJ, Abraham SM, Yaqub F, Luo L, Matutes E, Brito-Babapulle V, Vorechovsky I, Dyer MJ, Catovsky D. ATM is usually rearranged in T-cell prolymphocytic leukaemia. Oncogene. 1998 Feb 12;16(6):789-96. PMID:9488043 doi:https://dx.doi.org/10.1038/sj.onc.1201603
- ↑ Stoppa-Lyonnet D, Soulier J, Lauge A, Dastot H, Garand R, Sigaux F, Stern MH. Inactivation of the ATM gene in T-cell prolymphocytic leukemias. Blood. 1998 May 15;91(10):3920-6. PMID:9573030
- ↑ Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P. Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood. 1999 Jul 15;94(2):748-53. PMID:10397742
- ↑ Schaffner C, Idler I, Stilgenbauer S, Dohner H, Lichter P. Mantle cell lymphoma is characterized by inactivation of the ATM gene. Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2773-8. PMID:10706620 doi:https://dx.doi.org/10.1073/pnas.050400997
- ↑ Vorechovsky I, Luo L, Dyer MJ, Catovsky D, Amlot PL, Yaxley JC, Foroni L, Hammarstrom L, Webster AD, Yuille MA. Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia. Nat Genet. 1997 Sep;17(1):96-9. PMID:9288106 doi:https://dx.doi.org/10.1038/ng0997-96
- ↑ Stankovic T, Weber P, Stewart G, Bedenham T, Murray J, Byrd PJ, Moss PA, Taylor AM. Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia. Lancet. 1999 Jan 2;353(9146):26-9. PMID:10023947 doi:https://dx.doi.org/S0140-6736(98)10117-4
- ↑ Schaffner C, Stilgenbauer S, Rappold GA, Dohner H, Lichter P. Somatic ATM mutations indicate a pathogenic role of ATM in B-cell chronic lymphocytic leukemia. Blood. 1999 Jul 15;94(2):748-53. PMID:10397742
- ↑ Bullrich F, Rasio D, Kitada S, Starostik P, Kipps T, Keating M, Albitar M, Reed JC, Croce CM. ATM mutations in B-cell chronic lymphocytic leukemia. Cancer Res. 1999 Jan 1;59(1):24-7. PMID:9892178
- ↑ Matsuoka S, Rotman G, Ogawa A, Shiloh Y, Tamai K, Elledge SJ. Ataxia telangiectasia-mutated phosphorylates Chk2 in vivo and in vitro. Proc Natl Acad Sci U S A. 2000 Sep 12;97(19):10389-94. PMID:10973490 doi:https://dx.doi.org/10.1073/pnas.190030497
- ↑ Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature. 2003 Jan 30;421(6922):499-506. PMID:12556884 doi:https://dx.doi.org/10.1038/nature01368
- ↑ Ali A, Zhang J, Bao S, Liu I, Otterness D, Dean NM, Abraham RT, Wang XF. Requirement of protein phosphatase 5 in DNA-damage-induced ATM activation. Genes Dev. 2004 Feb 1;18(3):249-54. PMID:14871926 doi:https://dx.doi.org/10.1101/gad.1176004
- ↑ Bhoumik A, Takahashi S, Breitweiser W, Shiloh Y, Jones N, Ronai Z. ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Mol Cell. 2005 May 27;18(5):577-87. PMID:15916964 doi:https://dx.doi.org/10.1016/j.molcel.2005.04.015
- ↑ Kaygun H, Marzluff WF. Regulated degradation of replication-dependent histone mRNAs requires both ATR and Upf1. Nat Struct Mol Biol. 2005 Sep;12(9):794-800. Epub 2005 Aug 7. PMID:16086026 doi:https://dx.doi.org/10.1038/nsmb972
- ↑ Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF. Involvement of novel autophosphorylation sites in ATM activation. EMBO J. 2006 Aug 9;25(15):3504-14. Epub 2006 Jul 13. PMID:16858402 doi:https://dx.doi.org/7601231
- ↑ Sun Y, Xu Y, Roy K, Price BD. DNA damage-induced acetylation of lysine 3016 of ATM activates ATM kinase activity. Mol Cell Biol. 2007 Dec;27(24):8502-9. Epub 2007 Oct 8. PMID:17923702 doi:https://dx.doi.org/10.1128/MCB.01382-07
- ↑ Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K. ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage. J Biol Chem. 2010 Feb 12;285(7):4909-19. doi: 10.1074/jbc.M109.042341. Epub 2009 , Dec 4. PMID:19965871 doi:10.1074/jbc.M109.042341
- ↑ Stakyte K, Rotheneder M, Lammens K, Bartho JD, Gradler U, Fuchss T, Pehl U, Alt A, van de Logt E, Hopfner KP. Molecular basis of human ATM kinase inhibition. Nat Struct Mol Biol. 2021 Sep 23. pii: 10.1038/s41594-021-00654-x. doi:, 10.1038/s41594-021-00654-x. PMID:34556870 doi:https://dx.doi.org/10.1038/s41594-021-00654-x
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