Ataxia telangiectasia mutated
|ATM serine/threonine kinase|
|Symbols||; AT1; ATA; ATC; ATD; ATDC; ATE; TEL1; TELO1|
|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 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:
- "Entrez Gene: ATM ataxia telangiectasia mutated (includes complementation groups A, C and D)".
- Lee JH, Paull TT (December 2007). "Activation and regulation of ATM kinase activity in response to DNA double-strand breaks". Oncogene 26 (56): 7741–8. doi:10.1038/sj.onc.1210872. PMID 18066086.
- "Serine-protein kinase ATM - Homo sapiens (Human)".
- Lempiäinen H, Halazonetis TD (October 2009). "Emerging common themes in regulation of PIKKs and PI3Ks". EMBO J. 28 (20): 3067–73. doi:10.1038/emboj.2009.281. PMC 2752028. PMID 19779456.
- Huang X, Halicka HD, Darzynkiewicz Z (November 2004). "Detection of histone H2AX phosphorylation on Ser-139 as an indicator of DNA damage (DNA double-strand breaks)". Curr Protoc Cytom. Chapter 7: Unit 7.27. doi:10.1002/0471142956.cy0727s30. ISBN 0-471-14295-6. PMID 18770804.
- Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K et al. (September 1998). "Activation of the ATM kinase by ionizing radiation and phosphorylation of p53". Science 281 (5383): 1677–9. doi:10.1126/science.281.5383.1677. PMID 9733515.
- Morgan, David O. (2007). The cell cycle: Principles of Control. Oxford University Press. ISBN 0-19-920610-4.
- Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC et al. (2012). "Mitochondrial dysfunction in ataxia-telangiectasia". Blood 119 (6): 1490–500. doi:10.1182/blood-2011-08-373639. PMC 3286212. PMID 22144182.
- Bakkenist CJ, Kastan MB (January 2003). "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation". Nature 421 (6922): 499–506. doi:10.1038/nature01368. PMID 12556884.
- Canman CE, Lim DS (December 1998). "The role of ATM in DNA damage responses and cancer". Oncogene 17 (25): 3301–8. doi:10.1038/sj.onc.1202577. PMID 9916992.
- Banin S, Moyal L, Shieh S, Taya Y, Anderson CW, Chessa L et al. (September 1998). "Enhanced phosphorylation of p53 by ATM in response to DNA damage". Science 281 (5383): 1674–7. doi:10.1126/science.281.5383.1674. PMID 9733514.
- Kurz EU, Lees-Miller SP (2004). "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.
- Chen J (September 2000). "Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage". Cancer Res. 60 (18): 5037–9. PMID 11016625.
- Friedenson B (2007). "The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers". BMC Cancer 7: 152. doi:10.1186/1471-2407-7-152. PMC 1959234. PMID 17683622. Lay summary – Scientific Video Site.
- Chen G, Yuan SS, Liu W, Xu Y, Trujillo K, Song B et al. (April 1999). "Radiation-induced assembly of Rad51 and Rad52 recombination complex requires ATM and c-Abl". J. Biol. Chem. 274 (18): 12748–52. doi:10.1074/jbc.274.18.12748. PMID 10212258.
- Kishi S, Zhou XZ, Ziv Y, Khoo C, Hill DE, Shiloh Y et al. (August 2001). "Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks". J. Biol. Chem. 276 (31): 29282–91. doi:10.1074/jbc.M011534200. PMID 11375976.
- Shafman T, Khanna KK, Kedar P, Spring K, Kozlov S, Yen T et al. (May 1997). "Interaction between ATM protein and c-Abl in response to DNA damage". Nature 387 (6632): 520–3. doi:10.1038/387520a0. PMID 9168117.
- Kim ST, Lim DS, Canman CE, Kastan MB (Dec 1999). "Substrate specificities and identification of putative substrates of ATM kinase family members". J. Biol. Chem. 274 (53): 37538–43. doi:10.1074/jbc.274.53.37538. PMID 10608806.
- Wang Y, Cortez D, Yazdi P, Neff N, Elledge SJ, Qin J (April 2000). "BASC, a super complex of BRCA1-associated proteins involved in the recognition and repair of aberrant DNA structures". Genes Dev. 14 (8): 927–39. PMC 316544. PMID 10783165.
- Gatei M, Scott SP, Filippovitch I, Soronika N, Lavin MF, Weber B et al. (June 2000). "Role for ATM in DNA damage-induced phosphorylation of BRCA1". Cancer Res. 60 (12): 3299–304. PMID 10866324.
- Cortez D, Wang Y, Qin J, Elledge SJ (November 1999). "Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks". Science 286 (5442): 1162–6. doi:10.1126/science.286.5442.1162. PMID 10550055.
- Tibbetts RS, Cortez D, Brumbaugh KM, Scully R, Livingston D, Elledge SJ et al. (Dec 2000). "Functional interactions between BRCA1 and the checkpoint kinase ATR during genotoxic stress". Genes Dev. 14 (23): 2989–3002. doi:10.1101/gad.851000. PMC 317107. PMID 11114888.
- Gatei M, Zhou BB, Hobson K, Scott S, Young D, Khanna KK (May 2001). "Ataxia telangiectasia mutated (ATM) kinase and ATM and Rad3 related kinase mediate phosphorylation of Brca1 at distinct and overlapping sites. In vivo assessment using phospho-specific antibodies". J. Biol. Chem. 276 (20): 17276–80. doi:10.1074/jbc.M011681200. PMID 11278964.
- Beamish H, Kedar P, Kaneko H, Chen P, Fukao T, Peng C et al. (August 2002). "Functional link between BLM defective in Bloom's syndrome and the ataxia-telangiectasia-mutated protein, ATM". J. Biol. Chem. 277 (34): 30515–23. doi:10.1074/jbc.M203801200. PMID 12034743.
- Suzuki K, Kodama S, Watanabe M (September 1999). "Recruitment of ATM protein to double strand DNA irradiated with ionizing radiation". J. Biol. Chem. 274 (36): 25571–5. doi:10.1074/jbc.274.36.25571. PMID 10464290.
- Taniguchi T, Garcia-Higuera I, Xu B, Andreassen PR, Gregory RC, Kim ST et al. (May 2002). "Convergence of the fanconi anemia and ataxia telangiectasia signaling pathways". Cell 109 (4): 459–72. doi:10.1016/s0092-8674(02)00747-x. PMID 12086603.
- Reuter TY, Medhurst AL, Waisfisz Q, Zhi Y, Herterich S, Hoehn H et al. (October 2003). "Yeast two-hybrid screens imply involvement of Fanconi anemia proteins in transcription regulation, cell signaling, oxidative metabolism, and cellular transport". Exp. Cell Res. 289 (2): 211–21. doi:10.1016/s0014-4827(03)00261-1. PMID 14499622.
- Kang J, Ferguson D, Song H, Bassing C, Eckersdorff M, Alt FW et al. (January 2005). "Functional interaction of H2AX, NBS1, and p53 in ATM-dependent DNA damage responses and tumor suppression". Mol. Cell. Biol. 25 (2): 661–70. doi:10.1128/MCB.25.2.661-670.2005. PMC 543410. PMID 15632067.
- Fabbro M, Savage K, Hobson K, Deans AJ, Powell SN, McArthur GA et al. (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. 279 (30): 31251–8. doi:10.1074/jbc.M405372200. PMID 15159397.
- Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K et al. (Dec 1998). "ATM associates with and phosphorylates p53: mapping the region of interaction". Nat. Genet. 20 (4): 398–400. doi:10.1038/3882. PMID 9843217.
- Westphal CH, Schmaltz C, Rowan S, Elson A, Fisher DE, Leder P (May 1997). "Genetic interactions between atm and p53 influence cellular proliferation and irradiation-induced cell cycle checkpoints". Cancer Res. 57 (9): 1664–7. PMID 9135004.
- Bao S, Tibbetts RS, Brumbaugh KM, Fang Y, Richardson DA, Ali A et al. (June 2001). "ATR/ATM-mediated phosphorylation of human Rad17 is required for genotoxic stress responses". Nature 411 (6840): 969–74. doi:10.1038/35082110. PMID 11418864.
- Li S, Ting NS, Zheng L, Chen PL, Ziv Y, Shiloh Y et al. (July 2000). "Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response". Nature 406 (6792): 210–5. doi:10.1038/35018134. PMID 10910365.
- Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (April 2005). "Rheb binds and regulates the mTOR kinase". Curr. Biol. 15 (8): 702–13. doi:10.1016/j.cub.2005.02.053. PMID 15854902.
- Chang L, Zhou B, Hu S, Guo R, Liu X, Jones SN et al. (November 2008). "ATM-mediated serine 72 phosphorylation stabilizes ribonucleotide reductase small subunit p53R2 protein against MDM2 to DNA damage". Proc. Natl. Acad. Sci. U.S.A. 105 (47): 18519–24. doi:10.1073/pnas.0803313105. PMC 2587585. PMID 19015526.
- Kim ST, Xu B, Kastan MB (March 2002). "Involvement of the cohesin protein, Smc1, in Atm-dependent and independent responses to DNA damage". Genes Dev. 16 (5): 560–70. doi:10.1101/gad.970602. PMC 155347. PMID 11877376.
- Fernandez-Capetillo O, Chen HT, Celeste A, Ward I, Romanienko PJ, Morales JC et al. (Dec 2002). "DNA damage-induced G2-M checkpoint activation by histone H2AX and 53BP1". Nat. Cell Biol. 4 (12): 993–7. doi:10.1038/ncb884. PMID 12447390.
- Ward IM, Minn K, Jorda KG, Chen J (May 2003). "Accumulation of checkpoint protein 53BP1 at DNA breaks involves its binding to phosphorylated histone H2AX". J. Biol. Chem. 278 (22): 19579–82. doi:10.1074/jbc.C300117200. PMID 12697768.
- 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". Nature Reviews Molecular Cell Biology 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, Sedelnikova O, Newrock K, Bonner W (2002). "Histone H2A variants H2AX and H2AZ". Current Opinion in Genetics & Development 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". Nature Reviews 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, Kozlov S, Peng C, Chen P (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. doi:10.4161/cc.4.9.1981. 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