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Updated: Nov 12, 2025
Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
Published on: December 27, 2024
Cancer genome datamining and functional genetic analysis implicate mechanisms of ATM/ATR dysfunction underpinning
Erik Waskiewicz1, Michalis Vasiliou1, Isaac Corcoles-Saez1
1School of Medical Sciences and North West Cancer Research Institute, Bangor University, Bangor, UK.
Abstract:
ATM and ATR are conserved regulators of the DNA damage response linked to cancer. Comprehensive DNA sequencing efforts identified ~4,000 cancer-associated mutations in ATM/ATR; however, their cancer implications remain largely unknown. To gain insights, we identify functionally important conserved residues in ATM, ATR and budding yeast Mec1ATR via cancer genome datamining and a functional genetic analysis, respectively. Surprisingly, only a small fraction of the critical residues is in the active site of the respective enzyme complexes, implying that loss of the intrinsic kinase activity is infrequent in carcinogenesis. A number of residues are solvent accessible, suggestive of their involvement in interacting with a protein-partner(s). The majority, buried inside the respective enzyme complexes, might play a structural or regulatory role. Together, these findings identify evolutionarily conserved ATM, ATR, and Mec1ATR residues involved in diverse aspects of the enzyme function and provide fresh insights into the elusive genotype-phenotype relationships in ATM/ATR and their cancer-associated variants.
Insights
Researchers identified key residues in ATM and ATR DNA damage response proteins. Most mutations affecting these proteins in cancer do not impair kinase activity but may affect interactions or structure.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- ATM (Ataxia-Telangiectasia Mutated) and ATR (Ataxia-Telangiectasia and Rad3-Related) are crucial for the DNA damage response.
- Over 4,000 cancer-associated mutations in ATM/ATR have been identified, but their functional impact is largely unknown.
Purpose of the Study:
- To identify functionally important conserved residues in ATM, ATR, and Mec1ATR.
- To understand the implications of cancer-associated mutations in ATM/ATR.
Main Methods:
- Cancer genome datamining to identify conserved residues in ATM and ATR.
- Functional genetic analysis in budding yeast (Mec1ATR) to identify conserved residues.
Main Results:
- A small fraction of critical residues is located in the enzyme active sites, suggesting kinase activity loss is infrequent in cancer.
- Solvent-accessible residues may be involved in protein-protein interactions.
- Buried residues likely play structural or regulatory roles.
Conclusions:
- Identified evolutionarily conserved residues in ATM, ATR, and Mec1ATR involved in enzyme function.
- Provided insights into genotype-phenotype relationships for ATM/ATR and their cancer variants.
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