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A Robust Polymerase Chain Reaction-based Assay for Quantifying Cytosine-guanine-guanine Trinucleotide Repeats in Fragile X Mental Retardation-1 Gene
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ATM and ATR protect the genome against two different types of tandem repeat instability in Fragile X premutation mice

Ali Entezam1, Karen Usdin

  • 1Laboratory of Molecular and Cellular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA.

Nucleic Acids Research
|August 28, 2009
PubMed

Insights

Ataxia Telangiectasia-Mutated (ATM) protein prevents repeat expansions in Fragile X syndrome mouse models, distinct from ATR. ATM deficiency shows a paternal transmission and male offspring bias, suggesting sex-specific repair mechanisms.

Area of Science:

  • Genetics
  • Molecular Biology
  • Genomic Instability

Background:

  • Repeat expansion diseases, like Fragile X syndrome, stem from tandem repeat tract expansions in genes such as FMR1.
  • The ATM and Rad3-related (ATR) checkpoint kinase was previously shown to protect against repeat expansion in a Fragile X premutation mouse model.

Purpose of the Study:

  • To investigate the role of ATM in preventing repeat expansion in Fragile X premutation mouse models.
  • To determine if ATM-mediated prevention of repeat expansion differs from ATR-mediated mechanisms.

Main Methods:

  • Crossing Fragile X premutation mice with Ataxia Telangiectasia-Mutated (Atm) mutant mice.
  • Analyzing repeat expansion frequency based on parental transmission and offspring sex.

Main Results:

  • ATM deficiency significantly increases repeat expansion in Fragile X premutation mice.
  • The ATM-sensitive mechanism is distinct from the ATR-sensitive one.
  • ATM deficiency's effect is more pronounced with paternal transmission, and expansions are more frequent in male offspring.

Conclusions:

  • ATM plays a crucial role in preventing repeat expansion, independent of ATR.
  • Two distinct mechanisms for Fragile X repeat expansion exist: an ATR-sensitive pathway (maternal transmission) and an ATM-sensitive pathway (male expansion bias).
  • A sex-specific DNA repair mechanism, potentially X-linked, may contribute to the observed male bias in ATM-deficient mice.

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