DNA Damage Response and ATM Kinase Activation

The integrity of the genome is continuously challenged by endogenous and exogenous insults that induce DNA lesions, among which double-strand breaks (DSBs) are the most deleterious. Cells deploy a coordinated DNA damage response (DDR) to detect, signal and repair such lesions. At the apex of the DSB response is the ataxia-telangiectasia mutated (ATM) kinase, which exists as an inactive dimer under basal conditions. Upon break recognition by the MRE11-RAD50-NBS1 (MRN) sensor complex, ATM undergoes autophosphorylation and monomerisation, triggering its catalytic activation. Activated ATM phosphorylates a spectrum of substrates that orchestrate cell-cycle checkpoint arrest, chromatin remodelling and recruitment of core repair machinery. Downstream effectors include the tumour suppressor p53, the chromatin-bound protein KAP1 and histone H2AX, whose modification facilitates local chromatin relaxation and assembly of repair foci. In parallel, ATM responds to oxidative stress via redox-sensitive mechanisms that enhance its kinase activity. The interplay of these pathways ensures that damaged DNA is faithfully repaired by homologous recombination or non-homologous end joining, preserving genome stability. Dysregulation of ATM activation underlies radiosensitivity, cancer predisposition and neurodegeneration, and has stimulated efforts to modulate ATM for therapeutic gain in oncology and ageing disorders.

Research from Nature Portfolio

Recent high-resolution structural analysis has provided the first glimpse of the full-length ATM/Tel1 kinase in its native homodimeric form. Cryo-electron microscopy revealed how two protomers interface through the FAT and kinase domains, with extensive HEAT repeats packing against the catalytic core to impose an autoinhibited conformation. This structural framework explains how dimer dissociation and relief of steric hindrance enable substrate access and allosteric activation. In parallel, genome-wide cancer variant mapping has identified evolutionarily conserved ATM residues that are altered in tumours. Contrary to expectations, many of these mutations lie outside the active site, instead perturbing solvent-exposed surfaces or buried regulatory modules. Functional analyses suggest that these changes compromise protein-protein interactions or structural stability, offering insight into ATM-linked oncogenesis and revealing new targets for precision therapeutics.

DNA Damage Response and ATM Kinase Activation publication trend

The graph below shows the total number of articles in dna damage response and atm kinase activation across all publications each year (not limited to Nature Index journals).

Technical terms

ATM kinase: A serine/threonine kinase activated by DNA damage and oxidative stress that orchestrates checkpoint and repair signalling.

DNA double-strand break (DSB): A lesion in which both strands of the DNA helix are severed.

MRN complex: A trimeric sensor of DSBs composed of MRE11, RAD50 and NBS1 that recruits and activates ATM.

Autophosphorylation: A mechanism whereby a kinase phosphorylates itself to induce conformational changes and activation.

HEAT repeats: Tandem α-helical motifs that form a solenoid scaffold in ATM, regulating its interaction and assembly.

Post-translational modification (PTM): A covalent alteration of a protein after translation, such as phosphorylation or methylation, that modulates its function.

References

1. Disordered regions mediate the interaction of p53 and MRE11. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (2023).
2. Structure of the intact ATM/Tel1 kinase. Nature Communications (2016).
3. ATM’s Role in the Repair of DNA Double-Strand Breaks. Genes (2021).
4. A long noncoding RNA sensitizes genotoxic treatment by attenuating ATM activation and homologous recombination repair in cancers. PLOS Biology (2020).
5. Dual-functional significance of ATM-mediated phosphorylation of spindle assembly checkpoint component Bub3 in mitosis and the DNA damage response. Journal of Biological Chemistry (2022).
6. Cancer genome datamining and functional genetic analysis implicate mechanisms of ATM/ATR dysfunction underpinning carcinogenesis. Communications Biology (2021).