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Cause and consequences of genome instability in Huntington's Disease
Author(s) -
Lang Walter,
Majka Jerzy,
Owen Barbara,
Klugland Arne,
Bjoras Magnar,
McMurray Cynthia T.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.411.3
Subject(s) - msh2 , somatic cell , biology , genome instability , dna mismatch repair , dna repair , base excision repair , pms2 , transgene , gene , genetically modified mouse , genetics , dna damage , dna , germline , microbiology and biotechnology , cancer research
Mammalian cells have evolved sophisticated DNA repair systems to correct mispaired or damaged bases and extra helical loops. However, we find that two DNA repair systems, the mismatch recognition system (MMR) and the base excision repair, are turned into a causative factor rather than a safeguard of genomic integrity. We have followed CAG expansion in germ cells and in somatic tissues of transgenic mice harboring a fragment of the human Huntington's disease (HD) gene. CAG expansion of the hHD allele is abrogated in both somatic cells and in germ cells of transgenic mice that lack Msh2. A complex involving Msh2 is thought to cause expansions by binding to, but failing to correct at the site of DNA breaks. Base excision repair may cause the break that needs to be repaired. Surprisingly, expansion in somatic cells only occurs at midlife of the mouse. These data indicate that some process associated with aging causes expansion and DNA breaks only in midlife. We have purified the MSH2/MSH3 enzymes and examined their biochemical properties. We find that key steps of the MMR system are impaired and that other and repair pathways may be called into play to repair the site.