Messenger RNA levels were measured in actively dividing fibroblasts isolated from young, middle-age, and old-age humans and humans with progeria, a rare genetic disorder characterized by accelerated aging. Genes whose expression is associated with age-related phenotypes and diseases were identified. The data also suggest that an underlying mechanism of the aging process involves increasing errors in the mitotic machinery of dividing cells in the postreproductive stage of life. We propose that this dysfunction leads to chromosomal pathologies that result in misregulation of genes involved in the aging process.
Peptide nucleic acid (PNA) is a synthetic analogue of DNA and RNA, developed more than a decade ago in which the naturally occurring sugar phosphate backbone has been replaced by the N-(2-aminoethyl) glycine units. Unlike DNA or RNA in the unhybridized state (single strand) which can adopt a helical structure through base-stacking, although highly flexible, PNA does not have a well-defined conformational folding in solution. Herein, we show that a simple backbone modification at the gamma-position of the N-(2-aminoethyl) glycine unit can transform a randomly folded PNA into a helical structure. Spectroscopic studies showed that helical induction occurs in the C- to N-terminal direction and is sterically driven. This finding has important implication not only on the future design of nucleic acid mimics but also on the design of novel materials, where molecular organization and efficient electronic coupling are desired.
We report a high yielding synthesis of truly monodisperse, thiolate-protected silver clusters via a rationally designed approach. The cluster composition was determined by electrospray ionization (ESI) mass spectrometry to be Ag(7)(DMSA)(4), where DMSA represents meso-2,3-dimercaptosuccinic acid. The Ag(7) thiolate clusters exhibit distinct optical properties. The approach developed in this work provides some insight into the cluster growth kinetics and may be extendable to the synthesis of other sized silver nanoclusters.
Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as “undruggable”. We developed a decoy targeting STAT3 and performed a phase 0 trial. Expression levels of STAT3 target genes were decreased in the head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexa-ethyleneglycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development.
Developed in the early 1990's, PNA has emerged as a promising class of nucleic acid mimic because of its strong binding affinity and sequence selectivity towards DNA and RNA, and resistance to enzymatic degradation by proteases and nucleases; however, the main drawbacks, as compared to other classes of oligonucleotides, are water solubility and biocompatibility. Herein we show that installation of a relatively small, hydrophilic (R)-diethylene glycol (`miniPEG') unit at the γ-backbone transforms a randomly-folded PNA into a right-handed helix. Synthesis of optically pure R-MPγPNA monomers is described, which can be accomplished in a few simple steps from a commercially available and relatively cheap Boc-L-serine. Once synthesized, R-MPγPNA oligomers are preorganized into a right-handed helix and hybridize to DNA and RNA with greater affinity and sequence selectivity, and are more water soluble and less aggregating than the parental PNA oligomers. The results presented herein have important implications for the future design and application of PNA in biology, biotechnology and medicine, as well as in other disciplines including drug discovery and molecular engineering.
A series of anthraquinone-containing (AQ) DNA conjugates was prepared. In each case, the AQ is
linked to the 2‘-oxygen of a uridine. Physical and spectroscopic data suggest that the AQ is intercalated in the
duplex DNA on the 3‘-side of the uracil. Irradiation of the AQ-DNA conjugates with UV light results in
piperidine-requiring strand cleavage at GG steps of both the AQ-containing strand and its complement. The
AQ-conjugates were designed to have GG steps disposed symmetrically about the AQ intercalation site. The
distance dependence of reaction efficiency at GG steps following AQ irradiation was measured by means of
an AQ-containing 71 mer having 7 GG steps. The efficiency of reaction in this sequence falls off exponentially
with a distance dependence of 0.071 Å-1. AQ-containing conjugates were prepared that incorporate 7,8-dihydro-8-oxoguanines (8-OxoG) at various locations. 8-OxoG has a lower oxidation potential than any of the normal
DNA bases and serves as a trap for the migrating radical cation. The 8-OxoG is a very effective trap when the
radical cation must migrate through it to reach the GG step, it is a less effective trap when it is on the strand
complementary to the GG step. These findings support the mechanism for long-range radical cation migration
described as phonon-assisted polaron hopping.
The blood disorder, β-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the γ position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human β-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing γPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal of splenomegaly and up to 7% β-globin gene correction in HSCs, with extremely low off-target effects. The combination of nanoparticle delivery, next generation γPNAs and SCF treatment may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.