DNA repair gone wrong? The roles of the mismatch repair complexes MutSbeta and MutSalpha in repeat expansion in a mouse model of the Fragile X-related disorders

FARE Award Winner

Authors

• X-N Zhao
• R Lokanga
• D Kumari
• S Gupta
• D Wu
• W Yang
• K Usdin

Abstract

The Repeat Expansion Diseases are a group of 20+ human genetic disorders that arise from expansion of a single disease-specific microsatellite. The Fragile X (FX)-related disorders (FXDs) are members of this disease group in which the microsatellite repeat unit is CGG/CCG and the repeat tract is located in the 5’ UTR of the FMR1 gene. The individual strands of most of the disease-associated repeats, including the FX repeats, form hairpins that are thought to trigger expansion. The mismatch repair complexes MutSbeta and MutSalpha normally protect the genome against microsatellite instability. In this study, we investigated the role these proteins play in repeat expansion, a specialized form of microsatellite instability. We first carried out genetic studies by crossinga FXD mouse model with mice containing mutations in these proteins. Paradoxically, rather than protecting against expansions, we found that both MutSbeta and MutSalpha promote expansions although MutSalpha is only able to do so in a MutSbeta-dependent manner. In addition, MutSbeta also promotes large contractions. These activities suggest that these proteins may be acting to promote instability outside of canonical mismatch repair. We thus examined the in vitro interactions of the individual strands of FX repeats with purified human MutSbeta and MutSalpha. Using electrophoretic mobility shift and thermal denaturation assays we showed that both complexes bind to and stabilize the hairpins formed by repeats. These data along with previously published data from our laboratory suggest a model for how these proteins may be acting to promote repeat instability.

Scientific Focus Area: Genetics and Genomics

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