title: A MutSβ-Dependent Contribution of MutSα to Repeat Expansions in Fragile X Premutation Mice?
abstract: The fragile X-related disorders result from expansion of a CGG/CCG microsatellite in the 5' UTR of the FMR1 gene. We have previously demonstrated that the MSH2/MSH3 complex, MutSβ, that is important for mismatch repair, is essential for almost all expansions in a mouse model of these disorders. Here we show that the MSH2/MSH6 complex, MutSα also contributes to the production of both germ line and somatic expansions as evidenced by the reduction in the number of expansions observed in Msh6-/- mice. This effect is not mediated via an indirect effect of the loss of MSH6 on the level of MSH3. However, since MutSβ is required for 98% of germ line expansions and almost all somatic ones, MutSα is apparently not able to efficiently substitute for MutSβ in the expansion process. Using purified human proteins we demonstrate that MutSα, like MutSβ, binds to substrates with loop-outs of the repeats and increases the thermal stability of the structures that they form. We also show that MutSα facilitates binding of MutSβ to these loop-outs. These data suggest possible models for the contribution of MutSα to repeat expansion. In addition, we show that unlike MutSβ, MutSα may also act to protect against repeat contractions in the Fmr1 gene.
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Zhao
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.|Division of Medical Biochemistry, University of Cape Town Medical School, Cape Town, South Africa.
authors.forename: Rachel
authors.initials: R
authors.lastname: Lokanga
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kimaada
authors.initials: K
authors.lastname: Allette
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Inbal
authors.initials: I
authors.lastname: Gazy
authors.affiliation: Section on Physical Biochemistry, Laboratory of Biochemistry and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases. National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.affiliation: Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Karen
authors.initials: K
authors.lastname: Usdin
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics*; D005786:Gene Expression Regulation; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051719:MutS DNA Mismatch-Binding Protein / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D009841:Oligonucleotides / Q000235:genetics; D011506:Proteins / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051860:Fragile X Messenger Ribonucleoprotein 1; D051719:MutS DNA Mismatch-Binding Protein; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009841:Oligonucleotides; D011506:Proteins; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse; C094443:G-T mismatch-binding protein; C078444:MSH3 protein, human; C089762:Msh3 protein, mouse; C102997:Msh6 protein, mouse; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse