Nucleic acids are finding applications in nanotechnology as nanomaterials, mechanical devices, templates, and biosensors. G-quadruplex DNA, formed by π-π stacking of guanine (G) quartets, is an attractive alternative to regular B-DNA because of the kinetic and thermodynamic stability of quadruplexes. However, they suffer from a fatal flaw: the rules of recognition, i.e., the formation of a G-quartet in which four identical bases are paired, prevent the controlled assembly between different strands, leading to complex mixtures. In this report, we present the solution to this recognition problem. The proposed design combines two DNA elements: parallel-stranded duplexes and a quadruplex core. Parallel-stranded duplexes direct controlled assembly of the quadruplex core, and their strands present convenient points of attachments for potential modifiers. The exceptional stability of the quadruplex core provides integrity to the entire structure, which could be used as a building block for nucleic acid-based nanomaterials. As a proof of principle for the design's versatility, we assembled quadruplex-based 1D structures and visualized them using atomic force and transmission electron microscopy. Our findings pave the way to broader utilization of G-quadruplex DNA in structural DNA nanomaterials.
Identifying synthetic lethal interactions has emerged as a promising new therapeutic approach aimed at targeting cancer cells directly. Here, we used the yeast Saccharomyces cerevisiae as a simple eukaryotic model to screen for mutations resulting in a synthetic lethality with 5-amino-4-imidazole carboxamide ribonucleoside (AICAR) treatment. Indeed, AICAR has been reported to inhibit the proliferation of multiple cancer cell lines. Here, we found that loss of several histone-modifying enzymes, including Bre1 (histone H2B ubiquitination) and Set1 (histone H3 lysine 4 methylation), greatly enhanced AICAR inhibition on growth via the combined effects of both the drug and mutations on G1 cyclins. Our results point to AICAR impacting on Cln3 subcellular localization and at the Cln1 protein level, while the bre1 or set1 deletion affected CLN1 and CLN2 expression. As a consequence, AICAR and bre1/ set1 deletions jointly affected all three G1 cyclins (Cln1, Cln2, and Cln3), leading to a condition known to result in synthetic lethality. Significantly, these chemo-genetic synthetic interactions were conserved in human HCT116 cells. Indeed, knock-down of RNF40, ASH2L, and KMT2D/MLL2 induced a highly significant increase in AICAR sensitivity. Given that KMT2D/MLL2 is mutated at high frequency in a variety of cancers, this synthetic lethal interaction has an interesting therapeutic potential.KEYWORDS Synthetic lethality; histone modification; cell cycle; yeast; cancer cells D URING malignant progression, cancer cells acquire multiple mutations, including loss of function of tumor suppressors and gain of function of proto-oncogenes (Hanahan and Weinberg 2011) . These mutations are specific to cancer cells and absent in normal tissues. These changes can be exploited to specifically target and kill tumors while sparing the surrounding healthy cells. The identification of compounds causing synthetic lethality with particular mutations associated with cancer cells has thus emerged as a promising new therapeutic approach (Thompson et al. 2015). Synthetic lethality is defined as the interaction between coessential genes. As such, inhibition of their individual function has no effects on cell survival, while their coinhibition results in decreased cell proliferation or even cell death. Loss of gene function can be due to a mutation or achieved by chemical means. The combination of genetic and chemical inhibition by a specific drug is termed "chemo-genetic." Using the yeast Saccharomyces cerevisiae, we searched for mutations leading to synthetic lethality with the prodrug 5-amino-4-imidazole carboxamide ribonucleoside (AICAR).In cells, AICAR is metabolized into the monophosphate nucleotide form, ZMP (Supplemental Material, Figure S1A), a natural intermediate of the purine biosynthesis pathway (Daignan-Fornier and Pinson 2012) that is present in all cells, except in a few parasites lacking this pathway. In yeast cells, ZMP has been shown to play important regulatory roles at physiological concentrations (Rébora et al. 2001(Ré...
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