Ataxia telangiectasia mutated

Ataxia telangiectasia mutated (ATM) is a is_associated_with::serine/is_associated_with::threonine is_associated_with::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 is_associated_with::cell cycle arrest, is_associated_with::DNA repair or is_associated_with::apoptosis. Several of these targets, including is_associated_with::p53, is_associated_with::CHK2 and is_associated_with::H2AX are is_associated_with::tumor suppressors.

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

Introduction
Throughout the is_associated_with::cell cycle the DNA is monitored for damage. Damages result from errors during replication, by-products of metabolism, general toxic drugs or is_associated_with::ionizing radiation. The cell cycle has different is_associated_with::DNA damage checkpoints, which inhibit the next or maintain the current is_associated_with::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 is_associated_with::DNA damage, especially after is_associated_with::double-strand breaks (DSBs). ATM together with is_associated_with::NBS1 act as primary DSB sensor proteins. Different mediators, such as is_associated_with::Mre11 and is_associated_with::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 is_associated_with::CHK2 and is_associated_with::p53.

Structure
The ATM gene codes for a 350 kDa protein consisting of 3056 amino acids. ATM belongs to the superfamily of is_associated_with::Phosphatidylinositol 3-kinase-related kinases (PIKKs). The PIKK superfamily comprises six Ser/Thr-protein kinases that show a sequence similarity to is_associated_with::phosphatidylinositol 3-kinases (PI3Ks). This protein kinase family includes amongst others ATR (ATM- and RAD3-related), is_associated_with::DNA-PKcs (DNA-dependent protein kinase catalytic subunit) and is_associated_with::mTOR (mammalian target of rapamycin). Characteristic for ATM are five domains. These are from N-Terminus to C-Terminus the is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::tertiary structure, which has a curved, tubular shape present for example in the is_associated_with::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 is_associated_with::α-helix followed by a sharp turn, which is stabilized by a is_associated_with::disulfide bond.



Function
A complex of the three proteins is_associated_with::Mre11, RAD50 and is_associated_with::NBS1 (is_associated_with::Xrs2 in yeast), called the MRN complex in humans, recruits ATM to is_associated_with::double strand breaks (DSBs) and holds the two ends together. ATM directly interacts with the is_associated_with::NBS1 subunit and phosphorylates the histone variant is_associated_with::H2AX on Ser139. This phosphorylation generates binding sites for adaptor proteins with a is_associated_with::BRCT domain. These adaptor proteins then recruit different factors including the effector protein kinase is_associated_with::CHK2 and the tumor suppressor is_associated_with::p53. The ATM-mediated is_associated_with::DNA damage response consists of a rapid and a delayed response. The effector kinase is_associated_with::CHK2 is phosphorylated and thereby activated by ATM. Activated is_associated_with::CHK2 phosphorylates phosphatase is_associated_with::CDC25A, which is degraded thereupon and can no longer dephosphorylate is_associated_with::CDK2-is_associated_with::Cyclin, resulting in cell-cycle arrest. If the DSB can not be repaired during this rapid response, ATM additionally phosphorylates is_associated_with::MDM2 and is_associated_with::p53 at Ser15. p53 is also phosphorylated by the effector kinase is_associated_with::CHK2. These phosphorylation events lead to stabilization and activation of is_associated_with::p53 and subsequent transcription of numerous is_associated_with::p53 target genes including Cdk inhibitor is_associated_with::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.

Regulation
A functional is_associated_with::MRN complex is required for ATM activation after is_associated_with::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 is_associated_with::CHK2 and is_associated_with::p53. Inactive ATM is present in the cells without DSBs as dimers or multimers. Upon is_associated_with::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 (is_associated_with::MDC1) which binds to is_associated_with::MRE11, and the subsequent stimulation of kinase activity with the is_associated_with::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 is_associated_with::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
is_associated_with::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 is_associated_with::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, is_associated_with::apoptosis, G1/S, intra-S checkpoint and G2/M checkpoints, gene regulation, translation is_associated_with::initiation, and is_associated_with::telomere maintenance. Therefore a defect in ATM has severe consequences in repairing certain types of damage to DNA, and is_associated_with::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 is_associated_with::BRCA1 and its associated proteins following DNA damage. Certain kinds of is_associated_with::leukemias and is_associated_with::lymphomas, including is_associated_with::Mantle cell lymphoma, T-ALL, atypical is_associated_with::B cell chronic lymphocytic leukemia, and is_associated_with::T-PLL are also associated with ATM defects.

Meiosis
ATM functions during meiotic prophase. The wild-type ATM gene is expressed at a 4-fold increased level in human testes compared to is_associated_with::somatic cells (such as skin fibroblasts). In both mice and humans, ATM deficiency results in female and male is_associated_with::infertility. Deficient ATM expression causes severe meiotic disruption during prophase I. In addition, impaired ATM-mediated DNA double-strand break (DSB) repair has been identified as a likely cause of aging of mouse and human oocytes. Expression of the ATM gene, as well as other key DSB repair genes, declines with age in mouse and human oocytes and this decline is paralleled by an increase of DSBs in primordial follicles. These findings indicate that ATM-mediated homologous recombinational repair is a crucial function of meiosis.

Interactions
Ataxia telangiectasia mutated has been shown to interact with:


 * is_associated_with::Abl gene,
 * is_associated_with::BRCA1,
 * is_associated_with::Bloom syndrome protein,
 * is_associated_with::DNA-PKcs,
 * is_associated_with::FANCD2,
 * is_associated_with::MRE11A,
 * is_associated_with::Nibrin,
 * is_associated_with::P53,
 * is_associated_with::RAD17,
 * is_associated_with::RAD51,
 * is_associated_with::RBBP8,
 * is_associated_with::RHEB,
 * is_associated_with::RRM2B,
 * is_associated_with::SMC1A
 * is_associated_with::TERF1, and
 * is_associated_with::TP53BP1.