PMID: 9523530Apr 2, 1998Paper

Mutagenesis mediated by triple helix-forming oligonucleotides conjugated to psoralen: effects of linker arm length and sequence context

Photochemistry and Photobiology
M RahaP M Glazer

Abstract

Targeted mutagenesis and gene knock-out can be mediated by triple helix-forming oligonucleotides (TFO) linked to mutagenic agents, such as psoralen. However, this strategy is limited by the availability of homopurine/homopyrimidine stretches at or near the target site because such sequences are required for high-affinity triplex formation. To overcome this limitation, we have tested TFO conjugated to psoralen via linker arms of lengths varying from 2 to 86 bonds, thereby designed to deliver the psoralen at varying distances from the third strand binding site present at the 3' end of the supFG1 mutation reporter gene. Following triplex formation and UVA irradiation, mutations were detected using an SV40-based shuttle vector assay in human cells. The frequency and distribution of mutations depended on the length of the linker arm. Precise targeting was observed only for linker arms of length 2 and 6, which also yielded the highest mutation frequencies (3 and 14%, respectively). Psoralen-TFO with longer tethers yielded mutations at multiple sites, with the maximum distance from the triplex site limited by the linker length but with the distribution within that range influenced by the propensity for psoralen intercalation at A:T ba...Continue Reading

Citations

Jan 7, 2004·Mutation Research·Susanne Brendler-SchwaabDietmar Utesch
Apr 2, 2004·Biological & Pharmaceutical Bulletin·Fumi Nagatsugi, Shigeki Sasaki
Mar 19, 2002·Stem Cells·Paul D RichardsonClifford J Steer
Aug 21, 2010·Journal of Nucleic Acids·Rajagopal Krishnan, Dennis H Oh
May 4, 2004·Atherosclerosis. Supplements·Clifford J Steer, Betsy T Kren

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