General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase

Chemically modified peptide nucleic acids (PNAs) show great promise in the recognition of RNA duplexes by major-groove PNA·RNA–RNA triplex formation. Triplex formation is favored for RNA duplexes with a purine tract within one of the RNA duplex strands, and is severely destabilized if the purine tra...

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Main Authors: Ong, Alan Ann Lerk, Toh, Desiree-Faye Kaixin, Patil, Kiran M., Meng, Zhenyu, Yuan, Zhen, Krishna, Manchugondanahalli S., Devi, Gitali, Haruehanroengra, Phensinee, Lu, Yunpeng, Xia, Kelin, Okamura, Katsutomo, Sheng, Jia, Chen, Gang
Other Authors: Interdisciplinary Graduate School (IGS)
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/151002
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Institution: Nanyang Technological University
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spelling sg-ntu-dr.10356-1510022021-06-01T06:07:08Z General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase Ong, Alan Ann Lerk Toh, Desiree-Faye Kaixin Patil, Kiran M. Meng, Zhenyu Yuan, Zhen Krishna, Manchugondanahalli S. Devi, Gitali Haruehanroengra, Phensinee Lu, Yunpeng Xia, Kelin Okamura, Katsutomo Sheng, Jia Chen, Gang Interdisciplinary Graduate School (IGS) School of Physical and Mathematical Sciences School of Biological Sciences NTU Institute for Health Technologies Temasek Life Sciences Laboratory Science::Biological sciences Peptide Nucleic-acids Triplex-forming Oligonucleotides Chemically modified peptide nucleic acids (PNAs) show great promise in the recognition of RNA duplexes by major-groove PNA·RNA–RNA triplex formation. Triplex formation is favored for RNA duplexes with a purine tract within one of the RNA duplex strands, and is severely destabilized if the purine tract is interrupted by pyrimidine residues. Here, we report the synthesis of a PNA monomer incorporated with an artificial nucleobase S, followed by the binding studies of a series of S-modified PNAs. Our data suggest that an S residue incorporated into short 8-mer dsRNA-binding PNAs (dbPNAs) can recognize internal Watson–Crick C-G and U-A, and wobble U-G base pairs (but not G-C, A-U, and G-U pairs) in RNA duplexes. The short S-modified PNAs show no appreciable binding to DNA duplexes or single-stranded RNAs. Interestingly, replacement of the C residue in an S·C-G triple with a 5-methyl C results in the disruption of the triplex, probably due to a steric clash between S and 5-methyl C. Previously reported PNA E base shows recognition of U-A and A-U pairs, but not a U-G pair. Thus, S-modified dbPNAs may be uniquely useful for the general recognition of RNA U-G, U-A, and C-G pairs. Shortening the succinyl linker of our PNA S monomer by one carbon atom to have a malonyl linker causes a severe destabilization of triplex formation. Our experimental and modeling data indicate that part of the succinyl moiety in a PNA S monomer may serve to expand the S base forming stacking interactions with adjacent PNA bases. Ministry of Education (MOE) Nanyang Technological University We thank Prof. Tom Brown for providing us a detailed protocol for the synthesis of the S base. This work was supported by NTU start-up grant, Singapore Ministry of Education (MOE) Tier 1 grants (RGT3/13, RG42/15, and RG152/17), and MOE Tier 2 grants (MOE2013-T2-2-024 and MOE2015-T2-1-028) to G.C. The work was also supported by MOE Tier 1 (RG126/16 and RG31/18) and MOE Tier 2 (MOE2018-T2-1-033) to K.X. 2021-06-01T06:07:08Z 2021-06-01T06:07:08Z 2019 Journal Article Ong, A. A. L., Toh, D. K., Patil, K. M., Meng, Z., Yuan, Z., Krishna, M. S., Devi, G., Haruehanroengra, P., Lu, Y., Xia, K., Okamura, K., Sheng, J. & Chen, G. (2019). General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase. Biochemistry, 58(10), 1319-1331. https://dx.doi.org/10.1021/acs.biochem.8b01313 0006-2960 0000-0002-9887-128X 0000-0001-6198-390X 0000-0002-8772-9755 https://hdl.handle.net/10356/151002 10.1021/acs.biochem.8b01313 30775913 2-s2.0-85062457349 10 58 1319 1331 en RGT3/13 RG42/15 RG152/17 MOE2013-T2-2-024 MOE2015-T2-1-028 RG126/16 RG31/18 MOE2018-T2-1-033 Biochemistry © 2019 American Chemical Society. All rights reserved.
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Biological sciences
Peptide Nucleic-acids
Triplex-forming Oligonucleotides
spellingShingle Science::Biological sciences
Peptide Nucleic-acids
Triplex-forming Oligonucleotides
Ong, Alan Ann Lerk
Toh, Desiree-Faye Kaixin
Patil, Kiran M.
Meng, Zhenyu
Yuan, Zhen
Krishna, Manchugondanahalli S.
Devi, Gitali
Haruehanroengra, Phensinee
Lu, Yunpeng
Xia, Kelin
Okamura, Katsutomo
Sheng, Jia
Chen, Gang
General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
description Chemically modified peptide nucleic acids (PNAs) show great promise in the recognition of RNA duplexes by major-groove PNA·RNA–RNA triplex formation. Triplex formation is favored for RNA duplexes with a purine tract within one of the RNA duplex strands, and is severely destabilized if the purine tract is interrupted by pyrimidine residues. Here, we report the synthesis of a PNA monomer incorporated with an artificial nucleobase S, followed by the binding studies of a series of S-modified PNAs. Our data suggest that an S residue incorporated into short 8-mer dsRNA-binding PNAs (dbPNAs) can recognize internal Watson–Crick C-G and U-A, and wobble U-G base pairs (but not G-C, A-U, and G-U pairs) in RNA duplexes. The short S-modified PNAs show no appreciable binding to DNA duplexes or single-stranded RNAs. Interestingly, replacement of the C residue in an S·C-G triple with a 5-methyl C results in the disruption of the triplex, probably due to a steric clash between S and 5-methyl C. Previously reported PNA E base shows recognition of U-A and A-U pairs, but not a U-G pair. Thus, S-modified dbPNAs may be uniquely useful for the general recognition of RNA U-G, U-A, and C-G pairs. Shortening the succinyl linker of our PNA S monomer by one carbon atom to have a malonyl linker causes a severe destabilization of triplex formation. Our experimental and modeling data indicate that part of the succinyl moiety in a PNA S monomer may serve to expand the S base forming stacking interactions with adjacent PNA bases.
author2 Interdisciplinary Graduate School (IGS)
author_facet Interdisciplinary Graduate School (IGS)
Ong, Alan Ann Lerk
Toh, Desiree-Faye Kaixin
Patil, Kiran M.
Meng, Zhenyu
Yuan, Zhen
Krishna, Manchugondanahalli S.
Devi, Gitali
Haruehanroengra, Phensinee
Lu, Yunpeng
Xia, Kelin
Okamura, Katsutomo
Sheng, Jia
Chen, Gang
format Article
author Ong, Alan Ann Lerk
Toh, Desiree-Faye Kaixin
Patil, Kiran M.
Meng, Zhenyu
Yuan, Zhen
Krishna, Manchugondanahalli S.
Devi, Gitali
Haruehanroengra, Phensinee
Lu, Yunpeng
Xia, Kelin
Okamura, Katsutomo
Sheng, Jia
Chen, Gang
author_sort Ong, Alan Ann Lerk
title General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
title_short General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
title_full General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
title_fullStr General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
title_full_unstemmed General recognition of U‑G, U‑A, and C‑G pairs by double-stranded RNA-binding PNAs incorporated with an artificial nucleobase
title_sort general recognition of u‑g, u‑a, and c‑g pairs by double-stranded rna-binding pnas incorporated with an artificial nucleobase
publishDate 2021
url https://hdl.handle.net/10356/151002
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