CTG repeat instability and size variation timing in DNA repair-deficient mice
| Autor: | Albert Pastink, Claudine Junien, Geneviève Gourdon, Edith Brisson, Jeroen Essers, Roland Kanaar, Hein te Riele, Cédric Savouret |
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| Přispěvatelé: | Molecular Genetics |
| Rok vydání: | 2003 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Saccharomyces cerevisiae Proteins DNA Repair DNA repair Transgene RAD52 Mice Transgenic Biology Myotonic dystrophy General Biochemistry Genetics and Molecular Biology Mice medicine Animals Molecular Biology Repetitive Sequences Nucleic Acid Genetics General Immunology and Microbiology General Neuroscience DNA Helicases Articles medicine.disease Rad52 DNA Repair and Recombination Protein Chromatin DNA-Binding Proteins Mice Inbred C57BL DNA Repair Enzymes MSH2 DNA mismatch repair Homologous recombination |
| Zdroj: | EMBO Journal, 22(9), 2264-2273. Wiley-Blackwell |
| ISSN: | 1460-2075 0261-4189 |
| DOI: | 10.1093/emboj/cdg202 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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