Multipotent genetic suppression of retrotransposon-induced mutations by Nxf1 through fine-tuning of alternative splicing.
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.
Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America.
Dorothy
D
Concepcion
Lisbeth
L
Flores-García
Bruce A
BA
Hamilton
D017398:Alternative Splicing; D000818:Animals; D001259:Ataxia / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007426:Genes, Intracisternal A-Particle; D022861:Hermanski-Pudlak Syndrome / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D029543:Nucleocytoplasmic Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D010641:Phenotype; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D018626:Retroelements; D013489:Suppression, Genetic; D043222:Ubiquitin Thiolesterase / Q000235:genetics
D029543:Nucleocytoplasmic Transport Proteins; D012322:RNA Precursors; D016601:RNA-Binding Proteins; D018626:Retroelements; C469268:Usp14 protein, mouse; D043222:Ubiquitin Thiolesterase