title: Mutsβ generates both expansions and contractions in a mouse model of the Fragile X-associated disorders.
abstract: Fragile X-associated disorders are Repeat Expansion Diseases that result from expansion of a CGG/CCG-repeat in the FMR1 gene. Contractions of the repeat tract also occur, albeit at lower frequency. However, these contractions can potentially modulate disease symptoms or generate an allele with repeat numbers in the normal range. Little is known about the expansion mechanism and even less about contractions. We have previously demonstrated that the mismatch repair (MMR) protein MSH2 is required for expansions in a mouse model of these disorders. Here, we show that MSH3, the MSH2-binding partner in the MutSβ complex, is required for 98% of germ line expansions and all somatic expansions in this model. In addition, we provide evidence for two different contraction mechanisms that operate in the mouse model, a MutSβ-independent one that generates small contractions and a MutSβ-dependent one that generates larger ones. We also show that MutSβ complexes formed with the repeats have altered kinetics of ATP hydrolysis relative to complexes with bona fide MMR substrates and that MutSβ increases the stability of the CCG-hairpins at physiological temperatures. These data may have important implications for our understanding of the mechanism(s) of repeat instability and for the role of MMR proteins in this process.
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Zhao
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology.
authors.forename: Daman
authors.initials: D
authors.lastname: Kumari
authors.affiliation: Section on Structure and Mechanisms of DNA repair, replication and recombination, Laboratory of Molecular Biology and.
authors.forename: Shikha
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Section on Physical Biochemistry, Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0830, USA.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology.
authors.forename: Maya
authors.initials: M
authors.lastname: Evanitsky
authors.affiliation: Section on Structure and Mechanisms of DNA repair, replication and recombination, Laboratory of Molecular Biology and.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, ku@helix.nih.gov.
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D000818:Animals; D002460:Cell Line; D043171:Chromosomal Instability; D004195:Disease Models, Animal; D005260:Female; D005600:Fragile X Syndrome / Q000235:genetics* / Q000503:physiopathology; D018095:Germ-Line Mutation; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D051719:MutS DNA Mismatch-Binding Protein / Q000502:physiology*; D000074081:MutS Homolog 3 Protein; D009690:Nucleic Acid Conformation; D011485:Protein Binding; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D019680:Trinucleotide Repeat Expansion
chemical_list: C089762:Msh3 protein, mouse; D000074081:MutS Homolog 3 Protein; D011506:Proteins; D051719:MutS DNA Mismatch-Binding Protein