multipotent genetic suppression of retrotransposon-induced mutations by nxf1 through fine-tuning of alternative splicing多功能基因抑制retrotransposon-induced突变nxf1通过可变剪接的微调.pdfVIP

Multipotent Genetic Suppression of Retrotransposon- Induced Mutations by Nxf1 through Fine-Tuning of Alternative Splicing 1,2,3 ´ 1,2,3 1,2,3 Dorothy Concepcion , Lisbeth Flores-Garcıa , Bruce A. Hamilton * 1 Department of Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America, 2 Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, California, United States of America, 3 Rebecca and John Moores UCSD Cancer Center, University of California San Diego School of Medicine, La Jolla, California, United States of America Abstract 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 Nxf1CAST suppresses a specific and frequent class of intracisternal A particle (IAP)-induced mutations, including Ap3d1mh2J, a model for Hermansky-Pudlak syndrome, and Atcayhes, an orthologous gene model for Cayman ataxia, among others. The molecular phenotype of suppression includes ,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 som