Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.

• Main Authors: Dorothy Concepcion, Lisbeth Flores-García, Bruce A Hamilton
• Format: Article
• Language: English
• Published: Public Library of Science (PLoS) 2009-05-01
• Series: PLoS Genetics
• Online Access: http://europepmc.org/articles/PMC2674570?pdf=render
• ISSN: 1553-7390; 1553-7404

Cellular gene expression machinery has coevolved with molecular parasites, such as viruses and transposons, which rely on host cells for their expression and reproduction. We previously reported that a wild-derived allele of mouse Nxf1 (Tap), a key component of the host mRNA nuclear export machinery, suppresses two endogenous retrovirus-induced mutations and shows suggestive evidence of positive selection. Here we show that Nxf1(CAST) suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1(mh2J), a model for Hermansky-Pudlak syndrome, and Atcay(hes), an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes approximately two-fold increase in the level of correctly-spliced mRNA and a decrease in mutant-specific, alternatively-processed RNA accumulating from the inserted allele. Insertional mutations involving ETn and LINE elements are not suppressed, demonstrating a high degree of specificity to this suppression mechanism. These results implicate Nxf1 in some instances of pre-mRNA processing, demonstrate the useful range of Nxf1(CAST) alleles for manipulating existing mouse models of disease, and specifically imply a low functional threshold for therapeutic benefit in Cayman ataxia.