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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration
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Author Spotlight: Deciphering the Role of ATM in Ataxia-Telangiectasia and the Associated Cerebellar Degeneration

Published on: December 27, 2024

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Oxidative Damage Induced Telomere Mediated Genomic Instability in Cells from Ataxia Telangiectasia Patients

Prarthana Srikanth1,2, Amit Roy Chowdhury3, Grace Kah Mun Low1

  • 1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Genome Integrity
|November 29, 2023
PubMed

Insights

Ataxia telangiectasia mutated (ATM) protein is crucial for genome stability. Cells lacking ATM show telomere attrition and increased chromosome damage, especially under oxidative stress, highlighting ATM's role in telomere maintenance.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • The cellular genome is vulnerable to DNA damage, including single and double-strand breaks.
  • Ataxia telangiectasia mutated (ATM) protein is a key DNA damage sensor involved in DNA repair and telomere maintenance.
  • Deficiency in ATM leads to genomic instability and increased cancer susceptibility in Ataxia-Telangiectasia (AT) patients.

Purpose of the Study:

  • To characterize genome stability in cells from AT patients (AT -/- and AT +/-).
  • To compare DNA damage and genomic instability between normal (AT +/+) and AT -/- cells.
  • To investigate the role of ATM in telomere stability under oxidative stress.

Main Methods:

  • Characterization of genome stability in AT -/- and AT +/- cells.
  • Comparison of DNA damage and genomic instability markers between normal and AT -/- cells.
  • Assessment of sensitivity to sodium arsenite and ionizing radiation.
  • Comet-FISH and multicolor FISH analysis for telomeric instability and chromosome aberrations.
  • Peptide nucleic acid-FISH analysis for chromosome segregation.

Main Results:

  • AT -/- cells exhibited significant telomere attrition and increased spontaneous DNA damage.
  • AT -/- and AT +/- cells were sensitive to sodium arsenite and ionizing radiation-induced oxidative stress.
  • Telomeric fragments were detected in comet tails of AT -/- cells after exposure to stress agents, indicating telomeric instability.
  • Increased chromosome alterations, including complex aberrations, were observed in AT -/- cells.
  • Defective chromosome segregation was identified in ATM-deficient cells.

Conclusions:

  • ATM deficiency leads to pronounced telomere attrition and genomic instability.
  • ATM plays a critical role in maintaining telomere stability, particularly under conditions of oxidative stress.
  • The findings underscore the importance of ATM in preventing chromosomal abnormalities and maintaining genome integrity.
Keywords:
Ataxia Telangiectasia MutatedDNA Repair DeficiencyGenome InstabilityOxidative DamageTelomere Dynamics

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