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Article ; Online: End-ligation can dramatically stabilize i-motifs at neutral pH.

El-Khoury, Roberto / Damha, Masad J

Chemical communications (Cambridge, England)

2023 Volume 59, Issue 25, Page(s) 3715–3718

Abstract: Stabilizing i-motif structures at neutral pH and physiological temperature remains a major challenge. Here, we demonstrate the use of chemical end-ligation to stabilize intramolecular i-motifs at both acidic and neutral pH. We also demonstrate that ... ...

Abstract	Stabilizing i-motif structures at neutral pH and physiological temperature remains a major challenge. Here, we demonstrate the use of chemical end-ligation to stabilize intramolecular i-motifs at both acidic and neutral pH. We also demonstrate that combining 2'-deoxy-2'-fluoroarabinocytidine substitutions and end-ligation results in an i-motif with an unparalleled thermal stability of 54 °C at neutral pH. Overall, the ligated i-motifs presented herein may be used in screens for selective i-motif ligands and proteins and could find important applications in nanotechnology.
MeSH term(s)	Hydrogen-Ion Concentration ; Temperature
Language	English
Publishing date	2023-03-23
Publishing country	England
Document type	Journal Article
ZDB-ID	1472881-3
ISSN	1364-548X ; 1359-7345 ; 0009-241X
ISSN (online)	1364-548X
ISSN	1359-7345 ; 0009-241X
DOI	10.1039/d2cc07063d
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Article ; Online: 2'-Fluoro-arabinonucleic Acid (FANA): A Versatile Tool for Probing Biomolecular Interactions.

El-Khoury, Roberto / Damha, Masad J

Accounts of chemical research

2021 Volume 54, Issue 9, Page(s) 2287–2297

Abstract: This Account highlights the structural features that render 2'-deoxy-2'-fluoro-arabinonucleic acid (FANA) an ideal tool for mimicking DNA secondary structures and probing biomolecular interactions relevant to chemical biology.The high binding affinity of ...

Abstract	This Account highlights the structural features that render 2'-deoxy-2'-fluoro-arabinonucleic acid (FANA) an ideal tool for mimicking DNA secondary structures and probing biomolecular interactions relevant to chemical biology.The high binding affinity of FANA to DNA and RNA has had implications in therapeutics. FANA can hybridize to complementary RNA, resulting in a predominant A-form helix stabilized by a network of 2'F-H8(purine) pseudohydrogen bonding interactions. We have shown that FANA/RNA hybrids are substrates of RNase H and Ago2, both implicated in the mechanism of action of antisense oligonucleotides (ASOs) and siRNA, respectvely. This knowledge has helped us study the conformational preferences of ASOs and siRNA as well as crRNA in CRISPR-associated Cas9, thereby revealing structural features crucial to biochemical activity.Additionally, FANA is of particular use in stabilizing noncanonical DNA structures. For instance, we have taken advantage of the anti N-glycosidic bond conformation of FANA monomers to induce a parallel topology in telomeric G-quadruplexes. Subsequent single-molecule FRET studies elucidated the mechanism by which these parallel G-quadruplexes are recognized and extended by telomerase. Similarly, we have utilized FANA to stabilize elusive telomeric i-motifs in the presence of concomitant parallel G-quadruplexes and under physiological conditions, thereby reinforcing their potential relevance to telomere biology. In another study, we adapted microarray technology and used FANA substitutions to enhance the binding affinity of the G-quadruplex thrombin-binding aptamer to its thrombin target.Finally, we discovered that DNA polymerases can synthesize FANA strands from DNA templates. On the basis of this property, other groups demonstrated that FANA, like DNA, can store hereditary information. They did so by engineering polymerases to efficiently transfer genetic information from DNA to FANA and retrieve it back into DNA. Subsequent studies showed that FANA could be evolved to acquire ribozyme-like endonuclease or ligase activity and to form high-affinity aptamers.Overall, the implications of these studies are remarkable because they promise a deeper understanding of human biochemistry for innovative therapeutic avenues. This Account summarizes past achievements and provides an outlook for inspiring the increased use of FANA in biological applications and fostering interdisciplinary collaborations.
MeSH term(s)	Arabinonucleotides/biosynthesis ; Arabinonucleotides/chemistry ; DNA/chemistry ; DNA/metabolism ; DNA-Directed DNA Polymerase/metabolism ; Nucleic Acid Conformation ; RNA/chemistry ; RNA/metabolism
Chemical Substances	2'-deoxy-2'-fluoro-beta-D-arabinonucleic acid ; Arabinonucleotides ; RNA (63231-63-0) ; DNA (9007-49-2) ; DNA-Directed DNA Polymerase (EC 2.7.7.7)
Language	English
Publishing date	2021-04-16
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1483291-4
ISSN	1520-4898 ; 0001-4842
ISSN (online)	1520-4898
ISSN	0001-4842
DOI	10.1021/acs.accounts.1c00125
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Article ; Online: Challenges and Opportunities for Nucleic Acid Therapeutics.

Corey, David R / Damha, Masad J / Manoharan, Muthiah

Nucleic acid therapeutics

2021 Volume 32, Issue 1, Page(s) 8–13

Abstract: After decades overcoming difficult problems, antisense oligonucleotide (ASO), duplex RNA (siRNA), and messenger RNA (mRNA) nucleic acid therapeutic strategies are finally demonstrating clinical benefits. This success presents new challenges. What goals ... ...

Abstract	After decades overcoming difficult problems, antisense oligonucleotide (ASO), duplex RNA (siRNA), and messenger RNA (mRNA) nucleic acid therapeutic strategies are finally demonstrating clinical benefits. This success presents new challenges. What goals remain for basic research? Will there be an explosion of clinical applications that benefit many patients with different diseases, or will success be restricted to diseases that are ideal for the application of current technologies? The aim of this perspective is to describe a selection of the major goals for the next decade.
MeSH term(s)	Humans ; Oligonucleotides/genetics ; Oligonucleotides/therapeutic use ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/therapeutic use ; RNA, Messenger/genetics ; RNA, Messenger/therapeutic use ; RNA, Small Interfering/genetics ; RNA, Small Interfering/therapeutic use
Chemical Substances	Oligonucleotides ; Oligonucleotides, Antisense ; RNA, Messenger ; RNA, Small Interfering
Language	English
Publishing date	2021-12-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2639888-6
ISSN	2159-3345 ; 2159-3337
ISSN (online)	2159-3345
ISSN	2159-3337
DOI	10.1089/nat.2021.0085
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Article ; Online: Characterization of tRNA splicing enzymes RNA ligase and tRNA 2'-phosphotransferase from the pathogenic fungi Mucorales.

Ghosh, Shreya / Dantuluri, Swathi / Jacewicz, Agata / Sanchez, Ana M / Abdullahu, Leonora / Damha, Masad J / Schwer, Beate / Shuman, Stewart

RNA (New York, N.Y.)

2024 Volume 30, Issue 4, Page(s) 367–380

Abstract: Fungal Trl1 is an essential trifunctional tRNA splicing enzyme that heals and seals tRNA exons with 2',3'-cyclic- ... ...

Abstract	Fungal Trl1 is an essential trifunctional tRNA splicing enzyme that heals and seals tRNA exons with 2',3'-cyclic-PO
MeSH term(s)	Animals ; Humans ; Mucorales/genetics ; Mucorales/metabolism ; NAD/metabolism ; RNA/genetics ; RNA, Transfer/genetics ; RNA, Transfer/metabolism ; RNA Ligase (ATP)/genetics ; RNA Ligase (ATP)/metabolism ; Saccharomyces cerevisiae/metabolism ; Ligases ; Polynucleotide 5'-Hydroxyl-Kinase/chemistry ; RNA Splicing ; Mammals/genetics
Chemical Substances	NAD (0U46U6E8UK) ; RNA (63231-63-0) ; RNA, Transfer (9014-25-9) ; RNA Ligase (ATP) (EC 6.5.1.3) ; Ligases (EC 6.-) ; Polynucleotide 5'-Hydroxyl-Kinase (EC 2.7.1.78)
Language	English
Publishing date	2024-03-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	1241540-6
ISSN	1469-9001 ; 1355-8382
ISSN (online)	1469-9001
ISSN	1355-8382
DOI	10.1261/rna.079911.123
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Article ; Online: Sequence-Controlled Spherical Nucleic Acids: Gene Silencing, Encapsulation, and Cellular Uptake.

Kaviani, Sepideh / Fakih, Hassan H / Asohan, Jathavan / Katolik, Adam / Damha, Masad J / Sleiman, Hanadi F

Nucleic acid therapeutics

2023 Volume 33, Issue 4, Page(s) 265–276

Abstract: Antisense oligonucleotides (ASOs) can predictably alter RNA processing and control protein expression; however, challenges in the delivery of these therapeutics to specific tissues, poor cellular uptake, and endosomal escape have impeded progress in ... ...

Abstract	Antisense oligonucleotides (ASOs) can predictably alter RNA processing and control protein expression; however, challenges in the delivery of these therapeutics to specific tissues, poor cellular uptake, and endosomal escape have impeded progress in translating these agents into the clinic. Spherical nucleic acids (SNAs) are nanoparticles with a DNA external shell and a hydrophobic core that arise from the self-assembly of ASO strands conjugated to hydrophobic polymers. SNAs have recently shown significant promise as vehicles for improving the efficacy of ASO cellular uptake and gene silencing. However, to date, no studies have investigated the effect of the hydrophobic polymer sequence on the biological properties of SNAs. In this study, we created a library of ASO conjugates by covalently attaching polymers with linear or branched [dodecanediol phosphate] units and systematically varying polymer sequence and composition. We show that these parameters can significantly impact encapsulation efficiency, gene silencing activity, SNA stability, and cellular uptake, thus outlining optimized polymer architectures for gene silencing.
MeSH term(s)	Gene Silencing ; Nanoparticles/chemistry ; Nucleic Acids/genetics ; Nucleic Acids/chemistry ; Oligonucleotides, Antisense/genetics ; Oligonucleotides, Antisense/pharmacology ; Polymers
Chemical Substances	Nucleic Acids ; Oligonucleotides, Antisense ; Polymers
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2639888-6
ISSN	2159-3345 ; 2159-3337
ISSN (online)	2159-3345
ISSN	2159-3337
DOI	10.1089/nat.2022.0062
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Article ; Online: Synthesis of Chimeric Oligonucleotides Having Modified Internucleotide Linkages via an Automated H-Phosphonate/Phosphoramidite Approach.

Vlaho, Danielle / Damha, Masad J

Current protocols in nucleic acid chemistry

2018 Volume 73, Issue 1, Page(s) e53

Abstract: This article describes an automated solid-phase approach for the synthesis of chimeric oligonucleotides containing phosphoramidate-modified internucleotide linkages. An optimized H-phosphonate synthetic cycle is combined with the commonly used ... ...

Abstract	This article describes an automated solid-phase approach for the synthesis of chimeric oligonucleotides containing phosphoramidate-modified internucleotide linkages. An optimized H-phosphonate synthetic cycle is combined with the commonly used phosphoramidite approach to obtain oligonucleotides comprising blocks having various types of internucleotide linkages. This article is specific to the synthesis of oligonucleotides having phosphoramidate modifications, but is adaptable to permit the incorporation of other modified linkages accessible through H-phosphonate diester intermediates. © 2018 by John Wiley & Sons, Inc.
MeSH term(s)	Amides/chemistry ; Automation ; Esters/chemistry ; Oligonucleotides/chemical synthesis ; Oligonucleotides/chemistry ; Organophosphonates/chemistry ; Phosphoric Acids/chemistry ; Spectrometry, Mass, Electrospray Ionization
Chemical Substances	Amides ; Esters ; Oligonucleotides ; Organophosphonates ; Phosphoric Acids ; phosphoramidic acid (9Q189608GB)
Language	English
Publishing date	2018-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1934-9289
ISSN (online)	1934-9289
DOI	10.1002/cpnc.53
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Article ; Online: i-Motif folding intermediates with zero-nucleotide loops are trapped by 2'-fluoroarabinocytidine via F···H and O···H hydrogen bonds.

El-Khoury, Roberto / Macaluso, Veronica / Hennecker, Christopher / Mittermaier, Anthony K / Orozco, Modesto / González, Carlos / Garavís, Miguel / Damha, Masad J

Communications chemistry

2023 Volume 6, Issue 1, Page(s) 31

Abstract: G-quadruplex and i-motif nucleic acid structures are believed to fold through kinetic partitioning mechanisms. Such mechanisms explain the structural heterogeneity of G-quadruplex metastable intermediates which have been extensively reported. On the ... ...

Abstract	G-quadruplex and i-motif nucleic acid structures are believed to fold through kinetic partitioning mechanisms. Such mechanisms explain the structural heterogeneity of G-quadruplex metastable intermediates which have been extensively reported. On the other hand, i-motif folding is regarded as predictable, and research on alternative i-motif folds is limited. While TC
Language	English
Publishing date	2023-02-16
Publishing country	England
Document type	Journal Article
ZDB-ID	2929562-2
ISSN	2399-3669 ; 2399-3669
ISSN (online)	2399-3669
ISSN	2399-3669
DOI	10.1038/s42004-023-00831-7
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Article ; Online: Telomeric i-motifs and C-strands inhibit parallel G-quadruplex extension by telomerase.

El-Khoury, Roberto / Roman, Morgane / Assi, Hala Abou / Moye, Aaron L / Bryan, Tracy M / Damha, Masad J

Nucleic acids research

2023 Volume 51, Issue 19, Page(s) 10395–10410

Abstract: Telomeric C-rich repeated DNA sequences fold into tetrahelical i-motif structures in vitro at acidic pH. While studies have suggested that i-motifs may form in cells, little is known about their potential role in human telomere biology. In this study, we ...

Abstract	Telomeric C-rich repeated DNA sequences fold into tetrahelical i-motif structures in vitro at acidic pH. While studies have suggested that i-motifs may form in cells, little is known about their potential role in human telomere biology. In this study, we explore the effect of telomeric C-strands and i-motifs on the ability of human telomerase to extend G-rich substrates. To promote i-motif formation at neutral pH, we use telomeric sequences where the cytidines have been substituted with 2'-fluoroarabinocytidine. Using FRET-based studies, we show that the stabilized i-motifs resist hybridization to concomitant parallel G-quadruplexes, implying that both structures could exist simultaneously at telomeric termini. Moreover, through telomerase activity assays, we show that both unstructured telomeric C-strands and telomeric i-motifs can inhibit the activity and processivity of telomerase extension of parallel G-quadruplexes and linear telomeric DNA. The data suggest at least three modes of inhibition by C-strands and i-motifs: direct hybridization to the substrate DNA, hybridization to nascent product DNA resulting in early telomerase dissociation, and interference with the unique mechanism of telomerase unwinding and extension of a G-quadruplex. Overall, this study highlights a potential inhibitory role for the telomeric C-strand in telomere maintenance.
MeSH term(s)	Humans ; G-Quadruplexes ; Telomerase/metabolism ; DNA/chemistry ; Nucleic Acid Hybridization ; Telomere/metabolism
Chemical Substances	Telomerase (EC 2.7.7.49) ; DNA (9007-49-2)
Language	English
Publishing date	2023-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gkad764
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Zs.A 1067: Show issues

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Article ; Online: Large-Scale Photolithographic Synthesis of Chimeric DNA/RNA Hairpin Microarrays To Explore Sequence Specificity Landscapes of RNase HII Cleavage.

Lietard, Jory / Damha, Masad J / Somoza, Mark M

Biochemistry

2019 Volume 58, Issue 44, Page(s) 4389–4397

Abstract: Ribonuclease HII (RNase HII) is an essential endoribonuclease that binds to double-stranded DNA with RNA nucleotide incorporations and cleaves 5' of the ribonucleotide at RNA-DNA junctions. Thought to be present in all domains of life, RNase HII protects ...

Abstract	Ribonuclease HII (RNase HII) is an essential endoribonuclease that binds to double-stranded DNA with RNA nucleotide incorporations and cleaves 5' of the ribonucleotide at RNA-DNA junctions. Thought to be present in all domains of life, RNase HII protects genomic integrity by initiating excision repair pathways that protect the encoded information from rapid degradation. There is sparse evidence that the enzyme cleaves some substrates better than others, but a large-scale study is missing. Such large-scale studies can be carried out on microarrays, and we employ chemical photolithography to synthesize very large combinatorial libraries of fluorescently labeled DNA/RNA chimeric sequences that self-anneal to form hairpin structures that are substrates for
MeSH term(s)	DNA/chemical synthesis ; DNA/chemistry ; DNA/genetics ; Escherichia coli/enzymology ; Gene Library ; Hydrolysis ; Inverted Repeat Sequences ; Microarray Analysis ; RNA/chemical synthesis ; RNA/chemistry ; RNA/genetics ; Ribonuclease H/chemistry ; Substrate Specificity
Chemical Substances	RNA (63231-63-0) ; DNA (9007-49-2) ; ribonuclease HII (EC 3.1.26.-) ; Ribonuclease H (EC 3.1.26.4)
Language	English
Publishing date	2019-10-28
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.9b00806
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Zs.A 217: Show issues

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Article: Large-Scale Photolithographic Synthesis of Chimeric DNA/RNA Hairpin Microarrays To Explore Sequence Specificity Landscapes of RNase HII Cleavage

Lietard, Jory / Damha, Masad J / Somoza, Mark M

Biochemistry. 2019 Oct. 20, v. 58, no. 44

2019

Abstract: Ribonuclease HII (RNase HII) is an essential endoribonuclease that binds to double-stranded DNA with RNA nucleotide incorporations and cleaves 5′ of the ribonucleotide at RNA–DNA junctions. Thought to be present in all domains of life, RNase HII protects ...

Abstract	Ribonuclease HII (RNase HII) is an essential endoribonuclease that binds to double-stranded DNA with RNA nucleotide incorporations and cleaves 5′ of the ribonucleotide at RNA–DNA junctions. Thought to be present in all domains of life, RNase HII protects genomic integrity by initiating excision repair pathways that protect the encoded information from rapid degradation. There is sparse evidence that the enzyme cleaves some substrates better than others, but a large-scale study is missing. Such large-scale studies can be carried out on microarrays, and we employ chemical photolithography to synthesize very large combinatorial libraries of fluorescently labeled DNA/RNA chimeric sequences that self-anneal to form hairpin structures that are substrates for Escherichia coli RNase HII. The relative activity is determined by the loss of fluorescence upon cleavage. Each substrate includes a double-stranded 5 bp variable region with one to five consecutive ribonucleotide substitutions. We also examined the effect of all possible single and double mismatches, for a total of >9500 unique structures. Differences in cleavage efficiency indicate some level of substrate preference, and we identified the 5′-dC/rC-rA-dX-3′ motif in well-cleaved substrates. The results significantly extend known patterns of RNase HII sequence specificity and serve as a template using large-scale photolithographic synthesis to comprehensively map landscapes of substrate specificity of nucleic acid-processing enzymes.
Keywords	DNA ; DNA repair ; Escherichia coli ; RNA ; degradation ; fluorescence ; genomics ; information ; landscapes ; libraries ; microarray technology ; ribonucleases ; substrate specificity ; synthesis
Language	English
Dates of publication	2019-1020
Size	p. 4389-4397.
Publishing place	American Chemical Society
Document type	Article
Note	NAL-light
ZDB-ID	1108-3
ISSN	1520-4995 ; 0006-2960
ISSN (online)	1520-4995
ISSN	0006-2960
DOI	10.1021/acs.biochem.9b00806
Database	NAL-Catalogue (AGRICOLA)

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