CTG repeat instability and size variation timing in DNA repair-deficient mice

Type 1 myotonic dystrophy is caused by the expansion of an unstable CTG repeat in the DMPK gene. We have investigated the molecular mechanisms underlying the CTG repeat instability by crossing transgenic mice carrying >300 unstable CTG repeats in their human chromatin environment with mice knocko...

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Bibliographic Details
Published in:The EMBO journal 2003-05, Vol.22 (9), p.2264-2273
Main Authors: Gourdon, Geneviève, Savouret, Cédric, Brisson, Edith, Essers, Jeroen, Kanaar, Roland, Pastink, Albert, te Riele, Hein, Junien, Claudine
Format: Article
Language:English
Subjects:
Animals
CTG instability
DNA Helicases
DNA Repair - genetics
DNA Repair Enzymes
DNA-Binding Proteins - genetics
double-strand break repair
Mice
Mice, Inbred C57BL
Mice, Transgenic
mismatch repair
Rad52 DNA Repair and Recombination Protein
Repetitive Sequences, Nucleic Acid
Saccharomyces cerevisiae Proteins - genetics
transgenic mice
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Summary:Type 1 myotonic dystrophy is caused by the expansion of an unstable CTG repeat in the DMPK gene. We have investigated the molecular mechanisms underlying the CTG repeat instability by crossing transgenic mice carrying >300 unstable CTG repeats in their human chromatin environment with mice knockout for genes involved in various DNA repair pathways: Msh2 (mismatch repair), Rad52 and Rad54 (homologous recombination) and DNA‐PKcs (non‐homologous end‐joining). Genes of the non‐homologous end‐joining and homologous recombination pathways did not seem to affect repeat instability. Only lack of Rad52 led to a slight decrease in expansion range. Unexpectedly, the absence of Msh2 did not result in stabilization of the CTG repeats in our model. Instead, it shifted the instability towards contractions rather than expansions, both in tissues and through generations. Furthermore, we carefully analyzed repeat transmissions with different Msh2 genotypes to determine the timing of intergenerational instability. We found that instability over generations depends not only on parental germinal instability, but also on a second event taking place after fertilization.
ISSN:0261-4189
1460-2075
1460-2075
DOI:10.1093/emboj/cdg202