Janarthanan Jayawickramarajah

Molecular recognition via base-pairing

Hydrogen-bonding interactions in DNA/RNA systems are a defining feature of double helical systems. They also play a critical role in stabilizing other higher-order structures, such as hairpin loops, and thus in the broadest sense can be considered as key requisites to the successful translation and replication of genetic information. This importance, coupled with the aesthetic appeal of nucleic acid base (nucleobase) hydrogen-bond interactions, has inspired the use of such motifs to stabilize a range of synthetic structures. This, in turn, has led to the formation of a number of novel ensembles. This tutorial review will discuss these structures, both from a synthetic perspective and in terms of their potential application in areas that include, but are not limited to, self-assembled macrocyclic and high-order ensemble synthesis, supramolecular polymer preparation, molecular cage construction, and energy and electron transfer modeling.

Base-pairing mediated non-covalent polymers

The naturally occurring nucleic acid bases (nucleobases) adenine, thymine (uracil), guanine, and cytosine are widely appreciated for their ability to stabilize canonical Watson-Crick base-pairing motifs, as well as a number of other well-characterized arrangements, such as Hoogsteen and wobble heterodimers, and a variety of homodimers. In this tutorial review, the use of these kinds of interactions to form synthetic polymeric and oligomeric ensembles is summarized. Particular emphasis will be placed on synthetic analogues of guanine that stabilize the formation of well-defined higher order aggregates, as well as de novo polymeric systems whose properties are modulated by the presence of nucleobase derivatives incorporated within or attached to the chain-defining backbone. In both cases, nucleobase-nucleobase interactions serve to underlie the chemistry, establish the structural morphology, and enable the development of bioinspired, environmentally responsive materials.

Functions of lncRNA HOTAIR in lung cancer

Long non-coding RNAs (lncRNAs) govern fundamental biochemical and cellular processes. lncRNA HOX transcript antisense RNA (HOTAIR) represses gene expression through recruitment of chromatin modifiers. The expression of HOTAIR is elevated in lung cancer and correlates with metastasis and poor prognosis. Moreover, HOTAIR promotes proliferation, survival, invasion, metastasis, and drug resistance in lung cancer cells. Here we review the molecular mechanisms underlying HOTAIR-mediated aggressive phenotypes of lung cancer. We also discuss HOTAIR’s potential in diagnosis and treatment of lung cancer, as well as the challenges of exploiting HOTAIR for intervention of lung cancer.

Straightforward Self-Assembly of Porphyrin Nanowires in Water: Harnessing Adamantane/β-Cyclodextrin Interactions

A convenient approach for the self-assembly of well-defined porphyrin nanowires in water, wherein the individual monomers do not aggregate via pi-pi interactions, is disclosed. These unidirectional and heteromeric assemblies are instead composed of robust beta-CD/adamantane host/guest interactions. A combination of surface microscopies and fluorescence energy transfer experiments were conducted on the nanowires demonstrating their stability and resistance to disassembly.

Photophysical characterization of a cytidine–guanosine tethered phthalocyanine–fullerene dyad

A new non-covalent electron transfer model system, based on the use of cytidine-guanosine hydrogen bonding interactions, is described that incorporates a phthalocyanine photodonor and a C60 fullerene acceptor.

DNA-Small Molecule Chimera with Responsive Protein-Binding Ability

In this communication, we disclose a generalizable strategy for developing agents with regulable protein-binding ability. In particular, a responsive DNA-small molecule chimera (DC) 1 consisting of two synthetic protein-binding arms and a core oligonucleotide (ODN) domain is discussed. DC 1 can be cycled from a bidentate intramolecular quadruplex form to a monodentate duplex structure, via addition of external ODN stimuli. Importantly, these distinct secondary structures of 1 lead to significantly different protein-binding abilities, with the bidentate conformation showing a 20-fold enhancement (with a 0.8 microM dissociation constant, Kd) in trypsin-binding potency.

Functionalized base-pairs: versatile scaffolds for self-assembly

This article discusses the development of synthetic supramolecular systems derived from hydrogen bond driven base-pairing, with a focus on the self-assembly of individual nucleobase analogues.

Protein-binding molecular switches via host-guest stabilized DNA hairpins.

Molecular switches, with target protein-binding activity controlled by prior binding to specific input stimuli, are ubiquitously used in Nature. However, the emulation of such responsive systems, especially in a de novo fashion, remains a significant challenge. Herein, we disclose a strategy that harnesses an intramolecular β-CD/adamantane host-guest interaction to generate a stabilized DNA hairpin (ΔT(m) = 17 °C) that undergoes an input oligonucleotide (ODN)-selective structural transformation from a stem-loop conformation to a duplex. This ODN-induced conformational switch allows for the transition from an inactive state (wherein the adamantane protein-binding headgroup is encapsulated) to an activated protein-binding complex, with a freely accessible adamantane moiety. Given that hairpin domains can be readily modulated to be responsive to alternative ODN triggering sequences and that encapsulating macrocycles, such as β-CD, are good hosts for a number of protein-binding small molecules, this strategy may furnish a general method to develop ODN-responsive protein-binders.

Examination of the Effect of the Annealing Cation on Higher Order Structures Containing Guanine or Isoguanine Repeats

Isoguanine (2-oxo-6-amino-guanine), a natural but non-standard base, exhibits unique self-association properties compared to its isomer, guanine, and results in formation of different higher order DNA structures. In this work, the higher order structures formed by oligonucleotides containing guanine repeats or isoguanine repeats after annealing in solutions containing various cations are evaluated by electrospray ionization mass spectrometry (ESI-MS) and circular dichroism (CD) spectroscopy. The guanine-containing strand (G9) consistently formed quadruplexes upon annealing, whereas the isoguanine strand (Ig9) formed both pentaplexes and quadruplexes depending on the annealing cation. Quadruplex formation with G9 showed some dependence on the identity of the cation present during annealing with high relative quadruplex formation detected with six of ten cations. Analogous annealing experiments with Ig9 resulted in complex formation with all ten cations, and the majority of the resulting complexes were pentaplexes. CD results indicated most of the original complexes survived the desalting process necessary for ESI-MS analysis. In addition, several complexes, especially the pentaplexes, were found to be capable of cation exchange with ammonium ions. Ab initio calculations were conducted for isoguanine tetrads and pentads coordinated with all ten cations to predict the most energetically stable structures of the complexes in the gas phase. The observed preference of forming quadruplexes versus pentaplexes as a function of the coordinated cation can be interpreted by the calculated reaction energies of both the tetrads and pentads in combination with the distortion energies of tetrads.

Elevated expression of long intergenic non-coding RNA HOTAIR in a basal-like variant of MCF-7 breast cancer cells

Epigenetic regulation of gene expression is critical to phenotypic maintenance and transition of human breast cancer cells. HOX antisense intergenic RNA (HOTAIR) is a long intergenic non‐coding RNA that epigenetically represses gene expression via recruitment of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase. Elevated expression of HOTAIR promotes progression of breast cancer. In the current study we examined the expression and function of HOTAIR in MCF‐7‐TNR cells, a derivative of the luminal‐like breast cancer cell line MCF‐7 that acquired resistance to TNF‐α‐induced cell death. The expression of HOTAIR, markers of the luminal‐like and basal‐like subtypes, and growth were compared between MCF‐7 and MCF‐7‐TNR cells. These variables were further assessed upon inhibition of HOTAIR, EZH2, p38 MAPK, and SRC kinase in MCF‐7‐TNR cells. When compared with MCF‐7 cells, MCF‐7‐TNR cells exhibited an increase in the expression of HOTAIR, which correlated with characteristics of a luminal‐like to basal‐like transition as evidenced by dysregulated gene expression and accelerated growth. MCF‐7‐TNR cells exhibited reduced suppressive histone H3 lysine27 trimethylation on the HOTAIR promoter. Inhibition of HOTAIR and EZH2 attenuated the luminal‐like to basal‐like transition in terms of gene expression and growth in MCF‐7‐TNR cells. Inhibition of p38 and SRC diminished HOTAIR expression and the basal‐like phenotype in MCF‐7‐TNR cells. HOTAIR was robustly expressed in the native basal‐like breast cancer cells and inhibition of HOTAIR reduced the basal‐like gene expression and growth. Our findings suggest HOTAIR‐mediated regulation of gene expression and growth associated with the basal‐like phenotype of breast cancer cells.