Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice

Abstract

Huntington disease (HD), an autosomal dominant, progressive neurodegenerative disorder, is caused by an expanded CAG repeat sequence leading to an increase in the number of glutamine residues in the encoded protein. The normal CAG repeat range is 5-36, whereas 38 or more repeats are found in the diseased state; the severity of disease is roughly proportional to the number of CAG repeats. HD shows anticipation, in which subsequent generations display earlier disease onsets due to intergenerational repeat expansion. For longer repeat lengths, somatic instability of the repeat size has been observed both in human cases at autopsy and in transgenic mouse models containing either a genomic fragment of human HD exon 1 (ref. 9) or an expanded repeat inserted into the endogenous mouse gene Hdh (ref. 10). With increasing repeat number, the protein changes conformation and becomes increasingly prone to aggregation, suggesting important functional correlations between repeat length and pathology. Because dinucleotide repeat instability is known to increase when the mismatch repair enzyme MSH2 is missing, we examined instability of the HD CAG repeat by crossing transgenic mice carrying exon 1 of human HD (ref. 16) with Msh2-/- mice. Our results show that Msh2 is required for somatic instability of the CAG repeat.

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

“…This result suggests that in vivo, ⑀C residues could be more genotoxic than ⑀A. Therefore, hijacking of ANPG by ⑀C residues could be an important determinant of ⑀-adduct genotoxicity, and the following observations lend support for this hypothesis: (i) somatic instability of the CAG repeat in Huntington disease is based on hijacking of the mismatch repair protein Msh2 by DNA loop endogenously formed in the repeat region (58,59); (ii) the cell killing potency of DNA adducts generated by cisplatin is mediated by hijacking of the high mobility group domain proteins (60); (iii) the levels of ⑀A induced exogenously by vinyl chloride and vinyl carbamate are much higher than those of ⑀C (61); in contrast, the ratio of ⑀-adducts generated by endogenous LPO could be shifted toward ⑀C formation. It has been demonstrated that in ulcerative colitis, a chronic inflammatory condition associated with a predisposition to colon cancer, ⑀C levels were higher than in normal colon, whereas ⑀A was lower (62); also, in colon cancer biopsies, the level of ⑀C was 30 times higher than that of ⑀A (63).…”

DNA mismatch repair: Molecular mechanism, cancer, and ageing

“…MSH2-MSH3 also plays an important role in trinucleotide repeat expansion, the process that underlies several hereditary and progressive neurodegenerative diseases such as Huntington disease, myotonic dystrophy, and fragile-X syndrome (Cummings and Zoghbi, 2000). In the mouse, somatic and germline expansions of the CAG-CTG repeat within the Huntington's gene requires MSH2 (Kovtun and McMurray, 2001;Manley et al, 1999;Wheeler et al, 2003). Repeat instability is reduced in MSH3-null mice but elevated in MSH6-null mice pointing to a role for MSH3 in promoting repeat instability (van den Broek et al, 2002).…”

Evidence of cis-acting factors in replication-mediated trinucleotide repeat instability in primate cells

“…Longer rather than shorter nascent repeat tracts at Okazaki termini might form these structures more readily. The metabolism of the structural intermediates may lead to efficient or error-prone processing by replication 22,24,[32][33][34] , repair 37,46,47 or recombination proteins [43][44][45]48 , all of which could lead to instability. Although other explanations are possible, it is clear that striking differences in (CTG)•(CAG) stability result from the location of replication initiation relative to the repeat tract.…”