Ataxia telangiectasia mutated
|Ataxia telangiectasia mutated|
|External IDs||ChEMBL: GeneCards:|
Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2 and H2AX are tumor suppressors.
Throughout the cell cycle the DNA is monitored for damage. Damages result from errors during replication, by-products of metabolism, general toxic drugs or ionizing radiation. The cell cycle has different DNA damage checkpoints, which inhibit the next or maintain the current cell cycle step. There are two main checkpoints, the G1/S and the G2/M, during the cell cycle, which preserve correct progression. ATM plays a role in cell cycle delay after DNA damage, especially after double-strand breaks (DSBs). ATM together with NBS1 act as primary DSB sensor proteins. Different mediators, such as Mre11 and MDC1, acquire post-translational modifications which are generated by the sensor proteins. These modified mediator proteins then amplify the DNA damage signal, and transduce the signals to downstream effectors such as CHK2 and p53.
The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids. ATM belongs to the superfamily of Phosphatidylinositol 3-kinase-related kinases (PIKKs). The PIKK superfamily comprises six Ser/Thr-protein kinases that show a sequence similarity to phosphatidylinositol 3-kinases (PI3Ks). This protein kinase family includes amongst others ATR (ATM- and RAD3-related), DNA-PKcs (DNA-dependent protein kinase catalytic subunit) and mTOR (mammalian target of rapamycin). Characteristic for ATM are five domains. These are from N-Terminus to C-Terminus the HEAT repeat domain, the FRAP-ATM-TRRAP (FAT) domain, the kinase domain (KD), the PIKK-regulatory domain (PRD) and the FAT-C-terminal (FATC) domain. The HEAT repeats directly bind to the C-terminus of NBS1. The FAT domain interacts with ATM's kinase domain to stabilize the C-terminus region of ATM itself. The KD domain resumes kinase activity, while the PRD and the FATC domain regulate it. Although no structure for ATM has been solved, the overall shape of ATM is very similar to DNA-PKcs and is composed of a head and a long arm that is thought to wrap around double-stranded DNA after a conformational change. The entire N-terminal domain together with the FAT domain are predicted to adopt an α-helical structure, which was found by sequence analysis. This α-helical structure is believed to form a tertiary structure, which has a curved, tubular shape present for example in the Huntingtin protein, which also contains HEAT repeats. FATC is the C-terminal domain with a length of about 30 amino acids. It is highly conserved and consists of an α-helix followed by a sharp turn, which is stabilized by a disulfide bond.
A trimeric complex of the three proteins Mre11, RAD50 and NBS1 (Xrs2 in yeast), called the MRN complex in humans, recruits ATM to double strand breaks (DSBs) and holds the two ends together. ATM directly interacts with the NBS1 subunit and phosphorylates the histone variant H2AX on Ser139. This phosphorylation generates binding sites for adaptor proteins with a BRCT domain. These adaptor proteins then recruit different factors including the effector protein kinase CHK2 and the tumor suppressor p53. The ATM-mediated DNA damage response consists of a rapid and a delayed response. The effector kinase CHK2 is phosphorylated and thereby activated by ATM. Activated CHK2 phosphorylates phosphatase CDC25A, which is degraded thereupon and can no longer dephosphorylate CDK2-Cyclin, resulting in cell-cycle arrest. If the DSB can not be repaired during this rapid response, ATM additionally phosphorylates MDM2 and p53 at Ser15. p53 is also phosphorylated by the effector kinase CHK2. These phosphorylation events lead to stabilization and activation of p53 and subsequent transcription of numerous p53 target genes including Cdk inhibitor p21 which lead to long-term cell-cycle arrest or even apoptosis.
The protein kinase ATM may also be involved in mitochondrial homeostasis, as a regulator of mitochondrial autophagy (mitophagy) whereby old, dysfunctional mitochondria are removed. 
A functional MRN complex is required for ATM activation after double strand breaks (DSBs). The complex functions upstream of ATM in mammalian cells and induces conformational changes that facilitate an increase in the affinity of ATM towards its substrates, such as CHK2 and p53. Inactive ATM is present in the cells without DSBs as dimers or multimers. Upon DNA damage, ATM autophosphorylates on residue Ser1981. This phosphorylation provokes dissociation of ATM dimers, which is followed by the release of active ATM monomers. Further autophosphorylation (of residues Ser367 and Ser1893) is required for normal activity of the ATM kinase. Activation of ATM by the MRN complex is preceded by at least two steps, i.e. recruitment of ATM to DSB ends by the mediator of DNA damage checkpoint protein 1 (MDC1) which binds to MRE11, and the subsequent stimulation of kinase activity with the NBS1 C-terminus. The three domains FAT, PRD and FATC are all involved in regulating the activity of the KD kinase domain. The FAT domain interacts with ATM's KD domain to stabilize the C-terminus region of ATM itself. The FATC domain is critical for kinase activity and highly sensitive to mutagenesis. It mediates protein-protein interaction for example with the histone acetyltransferase TIP60 (HIV-1 Tat interacting protein 60 kDa), which acetylates ATM on residue Lys3016. The acetylation occurs in the C-terminal half of the PRD domain and is required for ATM kinase activation and for its conversion into monomers. While deletion of the entire PRD domain abolishes the kinase activity of ATM, specific small deletions show no effect.
Role in cancer 
Ataxia telangiectasia (AT) is a rare human disease characterized by cerebellar degeneration, extreme cellular sensitivity to radiation and a predisposition to cancer. All AT patients contain mutations in the ATM gene (ATM). Most other AT-like disorders are defective in genes encoding the MRN protein complex. One feature of the ATM protein is its rapid increase in kinase activity immediately following double-strand break formation. The phenotypic manifestation of AT is due to the broad range of substrates for the ATM kinase, involving DNA repair, apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation, translation initiation, and telomere maintenance. Therefore a defect in ATM has severe consequences in repairing certain types of damage to DNA, and cancer may result from improper repair. AT patients have an increased risk for breast cancer that has been ascribed to ATM's interaction and phosphorylation of BRCA1 and its associated proteins following DNA damage. Certain kinds of leukemias and lymphomas, including Mantle cell lymphoma, T-ALL, atypical B cell chronic lymphocytic leukemia, and T-PLL are also associated with ATM defects.
Ataxia telangiectasia mutated has been shown to interact with RAD17, RBBP8, RAD51, DNA-PKcs, RRM2B, FANCD2, Nibrin, TERF1, BRCA1, Abl gene, TP53BP1, MRE11A, P53, Bloom syndrome protein, SMC1A and RHEB.
See also 
- "Entrez Gene: ATM ataxia telangiectasia mutated (includes complementation groups A, C and D)".
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- Cortez, D; Wang Y, Qin J, Elledge S J (November 1999). "Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks". Science (UNITED STATES) 286 (5442): 1162–6. doi:10.1126/science.286.5442.1162. ISSN 0036-8075. PMID 10550055.
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- Shafman, T; Khanna K K, Kedar P, Spring K, Kozlov S, Yen T, Hobson K, Gatei M, Zhang N, Watters D, Egerton M, Shiloh Y, Kharbanda S, Kufe D, Lavin M F (May 1997). "Interaction between ATM protein and c-Abl in response to DNA damage". Nature (ENGLAND) 387 (6632): 520–3. doi:10.1038/387520a0. ISSN 0028-0836. PMID 9168117.
- Fernandez-Capetillo, Oscar; Chen Hua-Tang, Celeste Arkady, Ward Irene, Romanienko Peter J, Morales Julio C, Naka Kazuhito, Xia Zhenfang, Camerini-Otero R Daniel, Motoyama Noboru, Carpenter Phillip B, Bonner William M, Chen Junjie, Nussenzweig André (Dec. 2002). "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1". Nat. Cell Biol. (England) 4 (12): 993–7. doi:10.1038/ncb884. ISSN 1465-7392. PMID 12447390.
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- Kang, Jian; Ferguson David, Song Hoseok, Bassing Craig, Eckersdorff Mark, Alt Frederick W, Xu Yang (January 2005). "Functional Interaction of H2AX, NBS1, and p53 in ATM-Dependent DNA Damage Responses and Tumor Suppression". Mol. Cell. Biol. (United States) 25 (2): 661–70. doi:10.1128/MCB.25.2.661-670.2005. ISSN 0270-7306. PMC 543410. PMID 15632067.
- Fabbro, Megan; Savage Kienan, Hobson Karen, Deans Andrew J, Powell Simon N, McArthur Grant A, Khanna Kum Kum (July 2004). "BRCA1-BARD1 complexes are required for p53Ser-15 phosphorylation and a G1/S arrest following ionizing radiation-induced DNA damage". J. Biol. Chem. (United States) 279 (30): 31251–8. doi:10.1074/jbc.M405372200. ISSN 0021-9258. PMID 15159397.
- Khanna, K K; Keating K E, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller S P, Lavin M F (Dec. 1998). "ATM associates with and phosphorylates p53: mapping the region of interaction". Nat. Genet. (UNITED STATES) 20 (4): 398–400. doi:10.1038/3882. ISSN 1061-4036. PMID 9843217.
- Westphal, C H; Schmaltz C, Rowan S, Elson A, Fisher D E, Leder P (May 1997). "Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints". Cancer Res. (UNITED STATES) 57 (9): 1664–7. ISSN 0008-5472. PMID 9135004.
- Beamish, Heather; Kedar Padmini, Kaneko Hideo, Chen Philip, Fukao Toshiyuki, Peng Cheng, Beresten Sergei, Gueven Nuri, Purdie David, Lees-Miller Susan, Ellis Nathan, Kondo Naomi, Lavin Martin F (August 2002). "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM". J. Biol. Chem. (United States) 277 (34): 30515–23. doi:10.1074/jbc.M203801200. ISSN 0021-9258. PMID 12034743.
- Kim, Seong-Tae; Xu Bo, Kastan Michael B (March 2002). "Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage". Genes Dev. (United States) 16 (5): 560–70. doi:10.1101/gad.970602. ISSN 0890-9369. PMC 155347. PMID 11877376.
- Long, Xiaomeng; Lin Yenshou, Ortiz-Vega Sara, Yonezawa Kazuyoshi, Avruch Joseph (April 2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. (England) 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. ISSN 0960-9822. PMID 15854902.
Further reading 
- Giaccia AJ, Kastan MB (1998). "The complexity of p53 modulation: emerging patterns from divergent signals". Genes Dev. 12 (19): 2973–83. doi:10.1101/gad.12.19.2973. PMID 9765199.
- Kastan MB, Lim DS (2001). "The many substrates and functions of ATM". Nat. Rev. Mol. Cell Biol. 1 (3): 179–86. doi:10.1038/35043058. PMID 11252893.
- Shiloh Y (2002). "ATM: from phenotype to functional genomics--and back". Ernst Schering Res. Found. Workshop (36): 51–70. PMID 11859564.
- Redon C, Pilch D, Rogakou E, et al. (2002). "Histone H2A variants H2AX and H2AZ". Curr. Opin. Genet. Dev. 12 (2): 162–9. doi:10.1016/S0959-437X(02)00282-4. PMID 11893489.
- Tang Y (2003). "[ATM and Cancer]". Zhongguo Shi Yan Xue Ye Xue Za Zhi 10 (1): 77–80. PMID 12513844.
- Shiloh Y (2003). "ATM and related protein kinases: safeguarding genome integrity". Nat. Rev. Cancer 3 (3): 155–68. doi:10.1038/nrc1011. PMID 12612651.
- Gumy-Pause F, Wacker P, Sappino AP (2004). "ATM gene and lymphoid malignancies". Leukemia 18 (2): 238–42. doi:10.1038/sj.leu.2403221. PMID 14628072.
- Kurz EU, Lees-Miller SP (2005). "DNA damage-induced activation of ATM and ATM-dependent signaling pathways". DNA Repair (Amst.) 3 (8–9): 889–900. doi:10.1016/j.dnarep.2004.03.029. PMID 15279774.
- Abraham RT (2005). "The ATM-related kinase, hSMG-1, bridges genome and RNA surveillance pathways". DNA Repair (Amst.) 3 (8–9): 919–25. doi:10.1016/j.dnarep.2004.04.003. PMID 15279777.
- Lavin MF, Scott S, Gueven N, et al. (2005). "Functional consequences of sequence alterations in the ATM gene". DNA Repair (Amst.) 3 (8–9): 1197–205. doi:10.1016/j.dnarep.2004.03.011. PMID 15279808.
- Meulmeester E, Pereg Y, Shiloh Y, Jochemsen AG (2006). "ATM-mediated phosphorylations inhibit Mdmx/Mdm2 stabilization by HAUSP in favor of p53 activation". Cell Cycle 4 (9): 1166–70. PMID 16082221.
- Ahmed M, Rahman N (2006). "ATM and breast cancer susceptibility". Oncogene 25 (43): 5906–11. doi:10.1038/sj.onc.1209873. PMID 16998505.
- Drosophila telomere fusion - The Interactive Fly
- GeneReviews/NCBI/NIH/UW entry on Ataxia telangiectasia
- OMIM entries on Ataxia telangiectasia