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

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...

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Autores principales: Liu, Jing, Pendergraff, Hannah, Narayanannair, K. Jayaprakash, Lackey, Jeremy G., Kuchimanchi, Satya, Rajeev, Kallanthottathil G., Manoharan, Muthiah, Hu, Jiaxin, Corey, David R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794577/
https://www.ncbi.nlm.nih.gov/pubmed/23887934
http://dx.doi.org/10.1093/nar/gkt594
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author Liu, Jing
Pendergraff, Hannah
Narayanannair, K. Jayaprakash
Lackey, Jeremy G.
Kuchimanchi, Satya
Rajeev, Kallanthottathil G.
Manoharan, Muthiah
Hu, Jiaxin
Corey, David R.
author_facet Liu, Jing
Pendergraff, Hannah
Narayanannair, K. Jayaprakash
Lackey, Jeremy G.
Kuchimanchi, Satya
Rajeev, Kallanthottathil G.
Manoharan, Muthiah
Hu, Jiaxin
Corey, David R.
author_sort Liu, Jing
collection PubMed
description 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.
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spelling pubmed-37945772013-10-21 RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression Liu, Jing Pendergraff, Hannah Narayanannair, K. Jayaprakash Lackey, Jeremy G. Kuchimanchi, Satya Rajeev, Kallanthottathil G. Manoharan, Muthiah Hu, Jiaxin Corey, David R. Nucleic Acids Res Synthetic Biology and Chemistry 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. Oxford University Press 2013-10 2013-07-24 /pmc/articles/PMC3794577/ /pubmed/23887934 http://dx.doi.org/10.1093/nar/gkt594 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Synthetic Biology and Chemistry
Liu, Jing
Pendergraff, Hannah
Narayanannair, K. Jayaprakash
Lackey, Jeremy G.
Kuchimanchi, Satya
Rajeev, Kallanthottathil G.
Manoharan, Muthiah
Hu, Jiaxin
Corey, David R.
RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title_full RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title_fullStr RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title_full_unstemmed RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title_short RNA duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
title_sort rna duplexes with abasic substitutions are potent and allele-selective inhibitors of huntingtin and ataxin-3 expression
topic Synthetic Biology and Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3794577/
https://www.ncbi.nlm.nih.gov/pubmed/23887934
http://dx.doi.org/10.1093/nar/gkt594
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