The ATM gene, which stands for Ataxia-Telangiectasia Mutated, provides instructions for creating a protein that is widely distributed throughout the cell nucleus. This protein acts as a master regulator for maintaining the integrity of the cell’s genetic material. The ATM gene is located on chromosome 11, and the resulting protein is a type of enzyme known as a serine/threonine protein kinase. The primary purpose of the ATM protein is to respond rapidly when the cell’s DNA is damaged, specifically when both strands of the DNA helix are broken. When this gene is working correctly, it ensures that cells can effectively manage and repair this dangerous form of DNA damage.
The ATM Gene’s Role in DNA Damage Response
The ATM protein functions as a specialized sensor within the cell, constantly monitoring the state of the DNA. When a double-strand break occurs, the ATM protein is immediately activated from its normally inactive state. This activation typically involves its recruitment to the site of the break by a complex of other proteins, where it then undergoes a change in its structure, allowing it to become a functional enzyme.
Once activated, the ATM protein behaves like a central coordinator, initiating an extensive cellular response network. It does this by adding phosphate groups to a wide array of other proteins, a process known as phosphorylation. This phosphorylation acts like a switch, turning on or off dozens of downstream targets that are responsible for the subsequent steps of the DNA damage response.
One of the ATM protein’s most important actions is to enforce cell cycle checkpoint control, effectively pausing the cell’s division process. By phosphorylating and activating proteins like Chk2 and p53, the ATM protein ensures the cell cannot proceed to divide while its DNA is broken. This pause provides the necessary time for the cell’s repair machinery to fix the damage.
The ATM protein also directly facilitates the repair process by signaling to other proteins involved in both homologous recombination and non-homologous end joining, the two main pathways for fixing double-strand breaks. If the DNA damage is too extensive to be repaired, the ATM pathway can also trigger apoptosis, or programmed cell death. This self-destruction mechanism prevents a severely damaged cell from surviving and potentially becoming cancerous.
Ataxia-Telangiectasia Syndrome
When an individual inherits two non-functional copies of the ATM gene—one from each parent—they develop a severe, rare condition known as Ataxia-Telangiectasia (A-T). This is an autosomal recessive disorder, meaning the full syndrome only manifests when both copies of the gene are mutated, leading to little or no functional ATM protein. The lack of this protein means the body cannot effectively detect or repair double-strand DNA breaks, resulting in a state of profound genomic instability.
The inability to repair DNA damage particularly affects systems with high rates of cell division or high oxygen consumption, such as the nervous and immune systems. A hallmark of A-T is progressive cerebellar ataxia, which is a loss of muscle control and coordination due to the degeneration of Purkinje cells in the cerebellum. This neurological symptom often becomes noticeable in early childhood.
Another defining feature of the syndrome is the presence of telangiectasias, which are small, dilated blood vessels that often appear on the white of the eyes and on sun-exposed skin. Individuals with A-T also suffer from a severe immunodeficiency, making them highly susceptible to recurrent respiratory infections and predisposing them to certain cancers, specifically lymphomas and leukemias.
The Heterozygous State and Cancer Risk
The consequences of the ATM gene mutation are significantly different for individuals who inherit only one mutated copy, a state referred to as being heterozygous or a carrier. These individuals do not develop the full A-T syndrome because the single working copy of the gene is usually sufficient to produce enough functional ATM protein. However, having one reduced-function copy means their overall DNA repair capacity is less efficient.
This reduced efficiency in DNA repair leads to an increased lifetime risk for specific types of cancer, making the ATM gene a moderate-penetrance cancer susceptibility gene. The most well-documented association is with breast cancer in women, where the lifetime risk is estimated to be significantly higher than the average person, sometimes reaching up to 25%. The risk may also be elevated for male breast cancer.
Beyond breast cancer, carriers of a single ATM mutation have been found to have an elevated risk for pancreatic and prostate cancers. The lifetime risk for pancreatic cancer is estimated to be between 5% and 10% for carriers, substantially higher than the general population risk of about 1.5%. For men, the increased prostate cancer risk is also a concern. This elevated risk profile is thought to stem from the slow accumulation of unrepaired DNA damage over decades, eventually leading to the uncontrolled cell growth characteristic of cancer.