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Identification of Homologous Recombination Events in Mouse Embryonic Stem Cells Using Southern Blotting and Polymerase Chain Reaction
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Atm deficiency causes an increased frequency of intrachromosomal homologous recombination in mice

A J Bishop1, C Barlow, A J Wynshaw-Boris

  • 1Department of Cancer Cell Biology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

Cancer Research
|February 10, 2000
PubMed

Insights

Ataxia telangiectasia (AT) is linked to ATM gene mutations, causing DNA repair defects. Our mouse model shows complete Atm absence significantly increases genomic instability and recombination, potentially driving cancer in AT patients.

Area of Science:

  • Genetics
  • Molecular Biology
  • Cancer Research

Background:

  • Ataxia telangiectasia (AT) patients possess inactivating mutations in both copies of the ATM gene.
  • The ATM protein is crucial for recognizing DNA double-strand breaks (DSBs), with its absence delaying and reducing the p53 response.
  • AT patients exhibit a high cancer predisposition and chromosomal instability in their cells.

Purpose of the Study:

  • To investigate the role of functional Atm in maintaining genomic integrity using an in vivo mouse model.
  • To assess the frequency of intrachromosomal recombination and deletion events in the absence of Atm.

Main Methods:

  • Utilized an in vivo mouse model with the pink-eyed unstable mutation.
  • Compared the frequency of intrachromosomal recombination leading to deletion events in wild-type, heterozygous Atm, and mutant Atm mice.

Main Results:

  • The absence of functional Atm significantly elevated the frequency of intrachromosomal recombination resulting in deletion events (30.33% in mutant Atm vs. 17.73% in wild-type).
  • No significant increase in recombination frequency was observed in mice heterozygous for Atm (15.72%).

Conclusions:

  • These findings underscore the critical role of ATM in preserving genomic integrity following endogenous DNA damage.
  • Increased homologous recombination due to genomic instability in AT patients may contribute to carcinogenesis, especially given the prevalence of repetitive elements in the genome.

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