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User:Cellular Biochemistry II/Course 2010/ATM

< User:Cellular Biochemistry II‎ | Course 2010

Ataxia telangiectasia mutated (ATM) is a serine/threonine protein kinase (EC 2.7.11.1) 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.

The protein is named for the disorder Ataxia telangiectasia caused by mutations of ATM.[1]

Introduction edit

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 or maintain the next 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).[2] 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.

Structure edit

The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids.[3] 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 comprised 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 adobt 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 lenght 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.[4]

 
Schematic illustration of the four known conserved domains in four members of the PIKKs family.[4]

Function edit

A trimeric complex of the three proteins MRE11, RAD50 and NBS1 (XRS 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.[5] 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 phopsphorylated and thereby activated by ATM. Activated CHK2 phophorylates phosphatase CDC25A which is degraded thereupon and can no longer dephosphororylate CDK2-Cyclin resulting in cell-cycle arrest. If the DSB can not be repaired during this rapid response, ATM additionally phophorylates MDM2 and p53 at Ser15.[6] 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.[7]

 
ATM-mediated two-step response to DNA double strand breaks. In the rapid response activated ATM phosphorylates effector kinase CHK2 which phophphorylates CDC25A, targeting it for ubiquitination and degradation. Therefore phosphorylated CDK2-Cyclin accumulates and progression through the cell cycle is blocked. In the delayed response ATM phophorylates the inhibitor of p53, MDM2, and p53 which is also phosphorylated by Chk2. The resulting activation and stabilization of p53 leads to an increased expression of Cdk inhibitor p21, which futher helps to keep Cdk activity low and to maintain long-term cell cycle arrest.[7]

Regulation edit

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.[2] 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.[8] Further autophosphorylation (of residues Ser367 and Ser1893) is required for normal activity of the ATM kinase. Activation of ATM by the MRN complex is preceeded 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.[4]

Role in cancer edit

Ataxia telangiectasia (AT) is a rare human disease characterized by extreme cellular sensitivity to radiation and a predisposition to cancer. All AT patients contain mutations in the AT-mutated 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.[9][10] 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.[11] Therefore a defect in ATM has severe consequences, leading up to tumor formation. For example, the increased risk for breast cancer in AT patients has been implicated by the involvment of ATM in the interaction and phosphorylation of BRCA1 and its associated proteins following DNA damage.[12]

See also edit

References edit

<references> [4]

  1. ^ "Entrez Gene: ATM ataxia telangiectasia mutated (includes complementation groups A, C and D)".
  2. ^ a b 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.{{cite journal}}: CS1 maint: date and year (link)
  3. ^ "Serine-protein kinase ATM - Homo sapiens (Human)".
  4. ^ a b c d 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.{{cite journal}}: CS1 maint: date and year (link)
  5. ^ 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. PMID 18770804.{{cite journal}}: CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  6. ^ Canman CE, Lim DS, Cimprich KA; 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  7. ^ a b Cite error: The named reference MorganDavid was invoked but never defined (see the help page).
  8. ^ 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.{{cite journal}}: CS1 maint: date and year (link)
  9. ^ 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.{{cite journal}}: CS1 maint: date and year (link)
  10. ^ Banin S, Moyal L, Shieh S; 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: date and year (link) CS1 maint: multiple names: authors list (link)
  11. ^ 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.
  12. ^ 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.{{cite journal}}: CS1 maint: date and year (link)

[1]

  1. ^ Morgan, David O. (2007). The cell cylce: Principles of Control. Oxford University Press. ISBN 978-0-19-920610-0.
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