Mutsβ generates both expansions and contractions in a mouse model of the Fragile X-associated disorders
Xiao-Nan Zhao1, Daman Kumari1, Shikha Gupta2
1Section on Gene Structure and Disease, Laboratory of Cell and Molecular Biology.
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.
Insights
The mismatch repair protein MSH3 is crucial for Fragile X-associated disorder expansions. This study reveals MSH3
Area of Science:
- Genetics
- Molecular Biology
- Genomic Instability
Background:
- Fragile X-associated disorders stem from CGG/CCG-repeat expansions in the FMR1 gene.
- Repeat contractions also occur, potentially influencing disease severity or restoring normal repeat numbers.
- Mechanisms underlying repeat expansions and contractions remain largely unknown.
Purpose of the Study:
- Investigate the role of the mismatch repair (MMR) protein MSH3 in FMR1 repeat instability.
- Elucidate the mechanisms of both repeat expansions and contractions in a mouse model.
- Characterize the biochemical properties of MutSβ complexes with CGG repeats.
Main Methods:
- Utilized a mouse model of Fragile X-associated disorders.
- Assessed the requirement of MSH3 for germ line and somatic repeat expansions.
- Analyzed contraction mechanisms and MutSβ complex kinetics.
- Investigated MutSβ interaction with CCG-hairpin structures.
Main Results:
- MSH3 is essential for 98% of germ line and all somatic FMR1 repeat expansions.
- Identified two distinct contraction mechanisms: one MutSβ-independent (small contractions) and one MutSβ-dependent (large contractions).
- MutSβ exhibits altered ATP hydrolysis kinetics with repeats and enhances CCG-hairpin stability.
Conclusions:
- MSH3 plays a critical role in FMR1 repeat expansion, a key process in Fragile X-associated disorders.
- Distinct mechanisms govern repeat contractions, with MutSβ influencing larger contractions.
- MutSβ's interaction with CGG repeats suggests a direct role in modulating repeat instability.
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