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 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.
INSERM UR383, Hôpital Necker-Enfants Malades, Université Paris V, 149-161 rue de Sèvres, 75015 Paris, France.
Cédric
C
Savouret
Edith
E
Brisson
Jeroen
J
Essers
Roland
R
Kanaar
Albert
A
Pastink
Hein
H
te Riele
Claudine
C
Junien
Geneviève
G
Gourdon
D000818:Animals; D004265:DNA Helicases; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051721:Rad52 DNA Repair and Recombination Protein; D012091:Repetitive Sequences, Nucleic Acid; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
D004268:DNA-Binding Proteins; D051721:Rad52 DNA Repair and Recombination Protein; C497196:Rad52 protein, mouse; D029701:Saccharomyces cerevisiae Proteins; C075468:RAD54 protein, S cerevisiae; D004265:DNA Helicases; D045643:DNA Repair Enzymes