RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression

Jing Liu, Hannah Pendergraff, K. Jayaprakash Narayanannair, Jeremy G. Lackey, Satya Kuchimanchi, Kallanthottathil G. Rajeev, Muthiah Manoharan, Jiaxin Hu, David R. Corey

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Abasic substitutions within DNA or RNA are tools for evaluating the impact of absent nucleobases. Because of the importance of abasic sites in genetic damage, most research has involved DNA. Little information is available on the impact of abasic substitutions within RNA or on RNA interference (RNAi). Here, we examine the effect of abasic substitutions on RNAi and allele-selective gene silencing. Huntington's disease (HD) and Machado Joseph Disease (MJD) are severe neurological disorders that currently have no cure. HD and MJD are caused by an expansion of CAG repeats within one mRNA allele encoding huntingtin (HTT) and ataxin-3 (ATX-3) proteins. Agents that silence mutant HTT or ATX-3 expression would remove the cause of HD or MJD and provide an option for therapeutic development. We describe flexible syntheses for abasic substitutions and show that abasic RNA duplexes allele-selectively inhibit both mutant HTT and mutant ATX-3. Inhibition involves the RNAi protein argonaute 2, even though the abasic substitution disrupts the catalytic cleavage of RNA target by argonaute 2. Several different abasic duplexes achieve potent and selective inhibition, providing a broad platform for subsequent development. These findings introduce abasic substitutions as a tool for tailoring RNA duplexes for gene silencing.

Original languageEnglish (US)
Pages (from-to)8788-8801
Number of pages14
JournalNucleic acids research
Volume41
Issue number18
DOIs
StatePublished - Oct 2013

ASJC Scopus subject areas

  • Genetics

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    Liu, J., Pendergraff, H., Narayanannair, K. J., Lackey, J. G., Kuchimanchi, S., Rajeev, K. G., Manoharan, M., Hu, J., & Corey, D. R. (2013). RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression. Nucleic acids research, 41(18), 8788-8801. https://doi.org/10.1093/nar/gkt594