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CTG repeat instability and size variation timing in DNA repair‐deficient mice
Author(s) -
Savouret Cédric,
Brisson Edith,
Essers Jeroen,
Kanaar Roland,
Pastink Albert,
te Riele Hein,
Junien Claudine,
Gourdon Geneviève
Publication year - 2003
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/cdg202
Subject(s) - biology , myotonic dystrophy , homologous recombination , msh2 , genome instability , genetics , dna repair , non homologous end joining , trinucleotide repeat expansion , homologous chromosome , gene , dna mismatch repair , dna , microbiology and biotechnology , dna damage , allele
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.