Nuclear localization signal peptides for the import of plasmid DNA in gene therapy (review)

Abstract

Failure of cells to import specific proteins into nuclei can lead to carcinogenesis. Trafficking of nuclear proteins from the site of their synthesis in the cytoplasm to the sites of function in the nucleus through pore complexes is mediated by the presence of nuclear localization signals (NLSs) on proteins to be imported into nuclei. mRNA is exported through the same route as a complex with nuclear proteins. During gene therapy the foreign DNA needs to enter nuclei for its transcription in order to express the therapeutic protein; a pathway is proposed involving the complexation of plasmids and oligonucleotides with nascent nuclear proteins possessing NLSs as a prerequisite for their nuclear import. Covalent linkage of NLS peptides to oligonucleotides and plasmids or formation of complexes of plasmids with proteins possessing multiple NLS peptides is proposed to increase their import rates and the efficiency of gene expression. We suggest that cancer cells import more efficiently foreign DNA into nuclei compared with terminally differentiated cells because of their increased rates of proliferation and protein import and are easier targets for expression of foreign genes.