Genomic Stability and DNA Damage Responses in Ataxia-Telangiectasia

Ataxia-Telangiectasia (AT) is a recessive disorder caused by mutations in the ATM gene, which encodes a serine/threonine kinase central to the cellular response to DNA damage. ATM orchestrates detection of DNA double-strand breaks and coordinates repair through activation of downstream effectors, cell-cycle checkpoints and apoptosis. Loss of ATM function leads to genomic instability, immunodeficiency, heightened cancer risk and neurodegeneration. Beyond its nuclear role in DNA repair, ATM also influences cytoplasmic pathways controlling oxidative stress, mitochondrial homeostasis and metabolic regulation. In AT cells, persistent DNA lesions and defective signalling provoke accumulation of reactive oxygen species, mitochondrial dysfunction and impaired neuronal development. Understanding how ATM integrates DNA damage sensing with broader cellular networks is critical for elucidating the multi-system pathology of AT and for developing targeted therapies that restore genome integrity or alleviate secondary metabolic deficits.

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Genomic Stability and DNA Damage Responses in Ataxia-Telangiectasia publication trend

The graph below shows the total number of articles in genomic stability and dna damage responses in ataxia-telangiectasia across all publications each year (not limited to Nature Index journals).

Technical terms

ATM kinase: A protein enzyme that senses DNA double-strand breaks and phosphorylates key substrates to initiate repair and checkpoint signalling.

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed, posing a severe threat to genome integrity.

DNA damage response (DDR): A network of pathways that detect DNA lesions, halt cell-cycle progression and coordinate repair or apoptosis.

Oxidative stress: An imbalance between production of reactive oxygen species and the cell’s capacity to neutralise them, leading to molecular damage.

Mitochondrial dysfunction: Impairment of mitochondrial processes, including energy production and regulation of apoptosis, often linked to excess reactive oxygen species.

Reactive oxygen species (ROS): Chemically reactive molecules containing oxygen, which can damage proteins, lipids and nucleic acids when not adequately controlled.

References

1. The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway. Molecular Cancer (2024).
2. Ataxia Telangiectasia patient-derived neuronal and brain organoid models reveal mitochondrial dysfunction and oxidative stress. Neurobiology of Disease (2024).
3. New Views of the DNA Repair Protein Ataxia–Telangiectasia Mutated in Central Neurons: Contribution in Synaptic Dysfunctions of Neurodevelopmental and Neurodegenerative Diseases. Cells (2023).