Author URLs
Document Type
Article
Publication Date
2015
MeSH Terms
DNA Repair, DNA Polymerase beta
Subject: LCSH
Fragile X syndrome
Disciplines
Biology | Ecology and Evolutionary Biology
Abstract
The Fragile X-related disorders (FXDs) are members of the Repeat Expansion Diseases, a group of human genetic conditions resulting from expansion of a specific tandem repeat. The FXDs result from expansion of a CGG/CCG repeat tract in the 5’ UTR of the FMR1 gene. While expansion in a FXD mouse model is known to require some mismatch repair (MMR) proteins, our previous work and work in mouse models of another Repeat Expansion Disease show that early events in the base excision repair (BER) pathway play a role in the expansion process. One model for repeat expansion proposes that a non-canonical MMR process makes use of the nicks generated early in BER to load the MMR machinery that then generates expansions. However, we show here that heterozygosity for a Y265C mutation in Polβ, a key polymerase in the BER pathway, is enough to significantly reduce both the number of expansions seen in paternal gametes and the extent of somatic expansion in some tissues of the FXD mouse. These data suggest that events in the BER pathway downstream of the generation of nicks are also important for repeat expansion. Somewhat surprisingly, while the number of expansions is smaller, the average size of the residual expansions is larger than that seen in WT animals. This may have interesting implications for the mechanism by which BER generates expansions.
DOI
10.1371/journal.pgen.1005181
Repository Citation
Lokanga, Rachel Adihe; Senejani, Ali; Sweasy, Joann B.; and Usdin, Karen, "Heterozygosity for a Hypomorphic Polβ Mutation Reduces the Expansion Frequency in a Mouse Model of the Fragile X-Related Disorders" (2015). Biology and Environmental Science Faculty Publications. 51.
https://digitalcommons.newhaven.edu/biology-facpubs/51
Publisher Citation
Lokanga, R. A., Senejani, A. G., Sweasy, J. B., & Usdin, K. (2015). Heterozygosity for a Hypomorphic Polβ Mutation Reduces the Expansion Frequency in a Mouse Model of the Fragile X-Related Disorders. PLoS Genetics, 11(4), e1005181. http://doi.org/10.1371/journal.pgen.1005181
Comments
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.