The protein Ataxia-Telangiectasia Mutated, or ATM, is a protein kinase that plays a central role in maintaining genomic integrity. As a type of enzyme, it regulates the activity of other proteins. ATM is a primary regulator within the network that responds to severe forms of DNA damage, achieving this through a process known as phosphorylation.
Phosphorylation acts like a molecular switch. By adding a phosphate group—a small, charged chemical group—to a target protein, a kinase like ATM can alter that protein’s shape and function. This action allows a single activated protein to initiate a cascade of events. In the context of DNA damage, ATM’s ability to phosphorylate numerous targets allows it to coordinate a comprehensive response to protect the cell’s genetic blueprint.
The Trigger and Activation of ATM
The primary signal that activates ATM is the presence of DNA double-strand breaks (DSBs), where both strands of the DNA double helix are severed. These are among the most hazardous forms of DNA damage. If left unrepaired, DSBs can lead to the loss of large chromosome segments and cause genetic instability.
The initial detection of a DSB is performed by a group of proteins called the MRN complex, which consists of Mre11, Rad50, and Nbs1. This complex acts as a sensor, binding to the broken DNA ends. Once positioned, the MRN complex recruits ATM molecules to the site of the break, concentrating the kinase where it is needed for activation.
In its dormant state, ATM exists as an inactive dimer, meaning two identical ATM molecules are bound together. The recruitment to the DSB by the MRN complex brings these dimers into close proximity, which facilitates a conformational change. Aided by acetylation from the KAT5 (Tip60) enzyme and the helicase activity of the Rad50 subunit, the ATM molecules phosphorylate each other in a process called trans-autophosphorylation. This event causes the dimer to dissociate into two active, single-unit ATM monomers, ready to signal downstream.
Cellular Responses Orchestrated by ATM
Once activated, ATM monomers initiate a signaling cascade by phosphorylating hundreds of different proteins. This response leads to three major outcomes: pausing the cell’s division cycle, repairing the broken DNA, and triggering cell self-destruction if the damage is too severe. This coordinated strategy prevents the cell from passing damaged genetic information to its descendants.
An immediate consequence of ATM activation is the arrest of the cell cycle. ATM directly phosphorylates checkpoint proteins like the tumor suppressor p53 and the kinase CHK2. Phosphorylating p53 stabilizes it, allowing it to accumulate and turn on genes that halt cell division. Activated CHK2 also phosphorylates targets that block the cell cycle, providing time for DNA repair before replication or division.
Simultaneously, ATM sets the stage for the physical repair of the DNA break. One of its actions is the phosphorylation of a histone protein called H2AX. Histones are the proteins around which DNA is wound for compaction. When ATM phosphorylates H2AX at the site of a DSB, it creates a modified version known as gamma-H2AX (γH2AX). This modified histone acts as a beacon, attracting DNA repair proteins to the damaged chromatin and assembling the necessary molecular machinery.
If DNA damage is too widespread to be repaired, ATM signaling can lead to apoptosis, or programmed cell death. The sustained activation of p53 by ATM drives this process. When cell cycle arrest is prolonged and repair fails, high levels of active p53 induce genes that initiate the apoptotic pathway. This mechanism eliminates a damaged cell, preventing it from becoming cancerous.
The Role of ATM in DNA Repair Pathways
ATM also guides the specific method of DNA repair. The cell uses two main pathways for mending double-strand breaks: Non-Homologous End Joining (NHEJ) and Homologous Recombination (HR). NHEJ is a rapid process that directly joins broken DNA ends but can introduce errors. In contrast, HR is a more accurate method that uses an undamaged copy of the DNA from a sister chromatid as a template for repair.
The choice between these pathways is influenced by the cell cycle phase, with ATM’s activity being a deciding factor. HR is active in the S and G2 phases when a sister chromatid is available as a template. ATM promotes HR during these phases by phosphorylating proteins involved in end resection. This process trims one DNA strand at the break site to create a single-stranded overhang.
ATM directly phosphorylates the protein CtIP to begin end resection, initiating the steps that favor HR repair. This function biases the cell toward using the high-fidelity HR pathway when it is available. ATM also influences NHEJ by phosphorylating components of its machinery, such as the DNA-PKcs protein. This demonstrates a complex role in balancing both repair systems to suit the cell’s state.
Clinical Significance and Disease Implications
The genetic disorder Ataxia-Telangiectasia (A-T) is caused by inheriting two mutated, non-functional copies of the ATM gene. The loss of ATM’s protective functions leads to the symptoms of A-T. Patients experience progressive neurodegeneration, leading to movement and coordination problems (ataxia). They also suffer from immunodeficiency and have a high predisposition to cancers like lymphomas and leukemias.
Beyond A-T syndrome, the inactivation of ATM is a common event in the development of many sporadic cancers. As a tumor suppressor, ATM prevents the accumulation of mutations that drive cancer. When ATM is lost or inactivated, a cell becomes genetically unstable. This instability accelerates the rate at which it can acquire further mutations and evolve into a malignant tumor.
This connection to cancer has made ATM a target for therapeutic intervention. Researchers have developed ATM inhibitors, which are drugs that block the protein’s kinase activity. The strategy behind their use relies on a concept called synthetic lethality.
Many cancer cells are deficient in one DNA repair pathway, such as those with mutations in the BRCA genes. By using an ATM inhibitor to block a separate repair pathway, clinicians can cause the selective death of cancer cells. Healthy cells with intact repair systems are left relatively unharmed.