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ATM
ATM serine/threonine kinase
The ATM gene provides instructions for a protein vital for DNA repair and cell cycle regulation, impacting genomic stability, immune function, and neurological development. The ATM gene (ATM serine/threonine kinase) is essential for maintaining the integrity of the genome by coordinating the cell's response to DNA damage.
ATM is located on the long (q) arm of chromosome 11, at band 11q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The ATM gene, formally known as ATM serine/threonine kinase, plays a pivotal role in cellular processes, primarily focusing on DNA damage response and cell cycle control. The protein encoded by this gene functions as a master regulator, sensing DNA double-strand breaks and initiating repair pathways. This ensures the stability of genetic information within cells, which is crucial for preventing uncontrolled cell growth and maintaining normal tissue function.
Beyond its core function in DNA repair, the ATM protein also contributes to the development and activity of the nervous and immune systems. Its widespread cellular importance means that alterations in the ATM gene can have significant health consequences. Research has linked ATM variants to conditions like Ataxia-telangiectasia, a severe neurological disorder, and an increased risk for various cancers, including hereditary breast cancer. Understanding the ATM gene's multifaceted roles is key to comprehending its impact on human health.
What the gene does
The ATM gene encodes a serine/threonine kinase protein that acts as a central component of the DNA damage response (DDR) pathway. Its primary function involves detecting and signalling the presence of DNA double-strand breaks, which are highly deleterious forms of DNA damage. Upon sensing these breaks, the ATM protein phosphorylates a variety of downstream target proteins, initiating a cascade of events that halt the cell cycle and recruit repair machinery to the damaged site. This coordinated response is essential for maintaining genomic stability and preventing mutations.
Specifically, the ATM protein helps regulate the rate at which cells grow and divide, ensuring that damaged DNA is repaired before cell replication proceeds. It activates enzymes responsible for fixing broken DNA strands, thereby safeguarding the cell's genetic information. This regulatory role extends beyond DNA repair, influencing other critical cellular processes. The ATM protein is primarily located within the cell nucleus, where it can directly interact with DNA and chromatin structures.
Its involvement in the normal development and function of several bodily systems, particularly the nervous and immune systems, highlights its broad physiological importance. In the nervous system, ATM contributes to neuronal health and integrity. The central role of the ATM protein in both DNA repair and cell division makes it a significant focus in cancer research, as its malfunction can lead to genetic instability, a hallmark of cancer development.
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Chromosome location
The ATM gene is situated on the long arm of chromosome 11, specifically at position 11q22.3. This chromosomal location indicates its precise address within the human genome.
Protein structure
The ATM protein is a large protein, comprising 3056 amino acids, and exhibits a complex domain architecture crucial for its kinase activity and interactions. At its N-terminus, an Interaction with ABL1 region is located between amino acids 1373 and 1382, suggesting a regulatory role through interaction with the ABL1 kinase. Further along the protein, a large FAT (Focal Adhesion Targeting) domain spans amino acids 1940-2566. This domain is commonly found in phosphatidylinositol 3-kinase-related kinases (PIKKs) and is believed to mediate protein-protein interactions and subcellular localisation.
The core catalytic activity of ATM resides within the PI3K/PI4K catalytic domain, found between amino acids 2686 and 2998. This domain contains several critical regions, including the G-loop (amino acids 2692-2698), which is involved in ATP binding, and the Catalytic loop (amino acids 2867-2875), essential for phosphotransfer. An Activation loop (amino acids 2887-2911) within this catalytic domain is also vital for regulating the enzyme's activity. The ATM protein concludes with a C-terminal FATC (FAT C-terminal) domain, from amino acids 3024 to 3056, which is also characteristic of PIKKs and plays a role in regulating kinase function. Additionally, an atypical Microbody targeting signal is found between amino acids 3046 and 3048, potentially directing the protein to specific cellular compartments.
Key variants
Variants within the ATM gene encompass a wide spectrum of genetic changes, ranging from single nucleotide changes to larger deletions or insertions. These variants can lead to a non-functional or entirely absent ATM protein, disrupting its critical roles in DNA repair and cell signalling. The clinical impact of an ATM variant depends significantly on its nature and whether it results in a partial loss of function or a complete loss of protein activity. Individuals can inherit one or two altered copies of the ATM gene, leading to different clinical presentations and risk profiles. For instance, inheriting two pathogenic copies typically results in Ataxia-telangiectasia, while inheriting a single pathogenic copy is associated with an increased risk of certain cancers.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1122_1123del | p.Glu376fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1158del | p.Lys387fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1355del | p.Thr452fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1396C>T | p.Gln466Ter | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1402_1403del | p.Lys468fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1442T>G | p.Leu481Ter | Pathogenic | ★★★☆ | Ataxia-telangiectasia syndrome |
c.1564_1565del | p.Glu522fs | Pathogenic | ★★★☆ | Hereditary cancer-predisposing syndrome |
c.1607+1G>T | - | Pathogenic | ★★★☆ | Ataxia-telangiectasia syndrome |
c.1782del | p.Val595fs | Pathogenic | ★★★☆ | ATM-related cancer predisposition |
c.217_218del | p.Glu73fs | Pathogenic | ★★★☆ | Ataxia-telangiectasia syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ATM gene are associated with a range of health conditions, primarily due to its central role in DNA repair and genomic stability. The most well-known condition linked to biallelic (two copies) pathogenic ATM variants is Ataxia-telangiectasia, a severe autosomal recessive disorder characterised by progressive neurological degeneration and immune system dysfunction. Additionally, heterozygous (one copy) pathogenic variants in ATM are recognised as a moderate-penetrance risk factor for several cancers, including hereditary breast cancer, prostate cancer, pancreatic cancer, and ovarian cancer. The ATM gene is therefore implicated in both rare genetic syndromes and more common cancer predispositions.
Inheritance pattern
Conditions caused by pathogenic ATM variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ATM gene holds significant clinical relevance within the UK healthcare system, as evidenced by its inclusion in multiple NHS England Genomic Medicine Service (GMS) pathways and PanelApp green listings. Its importance in diagnosing and managing various conditions is highlighted by its presence on panels such as 'Adult solid tumours cancer susceptibility' and 'Inherited breast cancer and ovarian cancer'. The gene is also critical for diagnosing rare conditions like 'Ataxia telangiectasia - mutation testing' (R295) and 'Hereditary ataxia', reflecting its broad impact on neurological and oncological health. This widespread inclusion indicates that ATM testing is considered clinically appropriate and beneficial for specific patient groups within the UK.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research suggests that certain lifestyle factors may influence overall cancer risk in the general population, which could be particularly relevant for individuals with an increased genetic predisposition, such as those with ATM variants. Maintaining a balanced diet rich in fruits, vegetables, and whole grains is generally recommended, as these foods contain antioxidants and other compounds that may support cellular health. Regular physical activity has been consistently linked to a reduced risk of various cancers and is encouraged for overall well-being. Avoiding exposure to known carcinogens, such as tobacco smoke and excessive alcohol consumption, is also important for mitigating cancer risk. However, these are general health recommendations and do not specifically target the genetic mechanisms associated with ATM.
Supplement considerations
While numerous supplements are marketed for their purported health benefits, there is no conclusive scientific evidence to suggest that specific supplements can prevent or treat conditions associated with ATM gene variants. Antioxidant supplements, such as vitamins C and E, are sometimes discussed in the context of DNA protection, but their efficacy in individuals with ATM variants has not been established through robust clinical trials. Similarly, while some studies explore the role of various micronutrients in DNA repair pathways, these findings do not translate into specific recommendations for supplementation. Individuals should always consult with a healthcare professional before taking any supplements, particularly if they have a known genetic predisposition or are undergoing medical treatment, as some supplements can interact with medications or have unintended effects.
Frequently asked questions
What is the primary function of the ATM gene?
The ATM gene provides instructions for a protein that primarily acts as a master regulator in the cell's response to DNA double-strand breaks. It detects these breaks and initiates repair pathways to maintain genomic stability.
Which conditions are associated with ATM gene variants?
Pathogenic ATM variants are primarily associated with Ataxia-telangiectasia when two copies are altered. Inheriting one altered copy is linked to an increased risk of several cancers, including hereditary breast cancer.
Where is the ATM gene located?
The ATM gene is located on chromosome 11, specifically at position 11q22.3. This region is known to harbour genes important for various biological processes.
What is the ATM protein's role in the immune system?
The ATM protein plays an important role in the normal development and activity of the immune system.
Can lifestyle changes reduce risks associated with ATM variants?
While no specific lifestyle changes directly target ATM gene mechanisms, general healthy behaviours like a balanced diet, regular exercise, and avoiding carcinogens are broadly recommended for reducing overall cancer risk in the general population.
Are there supplements that can help with ATM-related conditions?
There is currently no conclusive scientific evidence that specific supplements can prevent or treat conditions associated with ATM gene variants. Any decision regarding supplements should always be made in consultation with a healthcare professional.
References
- Prokopcova J, Kleibl Z, Banwell CM. The role of ATM in breast cancer development. Breast cancer research and treatment. 2007. PMID: 17061036
- Lavin MF, Kozlov S. DNA damage-induced signalling in ataxia-telangiectasia and related syndromes. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2007. PMID: 17512070
- Kim JH, Kim H, Lee KY. Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk. Human molecular genetics. 2006. PMID: 16497724
- Renwick A, Thompson D, Seal S. ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nature genetics. 2006. PMID: 16832357
- Ahmed M, Rahman N. ATM and breast cancer susceptibility. Oncogene. 2006. PMID: 16998505
- Lavin MF, Birrell G, Chen P. ATM signaling and genomic stability in response to DNA damage. Mutation research. 2005. PMID: 15603757
- Thompson D, Duedal S, Kirner J. Cancer risks and mortality in heterozygous ATM mutation carriers. Journal of the National Cancer Institute. 2005. PMID: 15928302
- Hall J. The Ataxia-telangiectasia mutated gene and breast cancer: gene expression profiles and sequence variants. Cancer letters. 2005. PMID: 16112413
- Kitagawa R, Kastan MB. The ATM-dependent DNA damage signaling pathway. Cold Spring Harbor symposia on quantitative biology. 2005. PMID: 16869743
- Gumy-Pause F, Wacker P, Sappino AP. ATM gene and lymphoid malignancies. Leukemia. 2004. PMID: 14628072
- Motoyama N, Naka K. DNA damage tumor suppressor genes and genomic instability. Current opinion in genetics & development. 2004. PMID: 15108799
- Kurz EU, Lees-Miller SP. DNA damage-induced activation of ATM and ATM-dependent signaling pathways. DNA repair. 2004. PMID: 15279774
- McKinnon PJ. ATM and ataxia telangiectasia. EMBO reports. 2004. PMID: 15289825
- Shiloh Y. ATM and related protein kinases: safeguarding genome integrity. Nature reviews. Cancer. 2003. PMID: 12612651
- Bradbury JM, Jackson SP. ATM and ATR. Current biology : CB. 2003. PMID: 12814562
- Yang J, Yu Y, Hamrick HE. ATM, ATR and DNA-PK: initiators of the cellular genotoxic stress responses. Carcinogenesis. 2003. PMID: 12919958
- Geoffroy-Perez B, Janin N, Ossian K. Cancer risk in heterozygotes for ataxia-telangiectasia. International journal of cancer. 2001. PMID: 11410879