Chemists have found a way to glue together DNA and RNA strands using a purely chemical reaction—called click ligation—that works on any scale, under a wide range of conditions, and produces an artificial linkage that cells can still read. This matters because the standard biological method for joining DNA strands is finicky: it only works on natural DNA, requires specific conditions, and cannot easily incorporate chemical modifications. Researchers studying gene regulation, epigenetics, and viral replication need to build large, modified DNA and RNA constructs to probe how genes are switched on and off—mechanisms that go awry in cancer and ageing. Current tools cannot make those constructs reliably or at scale. If successful, click ligation will let scientists assemble synthetic genes containing methylated bases, quadruplex structures, or fluorescent labels. They can then use super-resolution microscopy to watch how DNA loops and chromatin packaging control protein production, and single-molecule FRET to track how influenza virus copies itself. The project also aims to build artificial molecular machines that carry out controlled chemical reactions, potentially leading to new ways to synthesise drugs. This is fundamental chemistry-driven biotechnology; its immediate payoff is better tools for molecular biology, not a direct consumer product.
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This project introduces a new paradigm into nucleic acids research, 'click ligation', which is an extremely efficient purely chemical (as opposed to biological) method for joining DNA and RNA strands to make large biologically active constructs (DNA and RNA are the molecules in cells that store and transmit genetic information). Although the new chemistry produces an unnatural linkage, it can be read through by DNA polymerases, the enzymes that make new copies of DNA in living systems during cell division. Thus our new artificial DNA linkage is truly biocompatible. Unlike biological ligation, this chemical reaction can be carried out on both normal and chemically-modified DNA, on any scale under a wide range of physical conditions. This makes it useful for biotechnology, i.e. the large scale production of medicinally important biological constructs. We will use click ligation to make very long DNA strands, enabling the assembly of chemically-modified synthetic genes which can be used to make proteins. Our work will allow the insertion of structural motifs such as quadruplexes and chemical modifications such as methylated and hydroxymethylated bases into genes for the study of gene expression and epigenetics. These modifications are thought to switch genes on and off by mechanisms that are not yet fully understood. They are currently the focus of intense research as aberrant genetic switches are implicated in diseases such as cancer and also in ageing. We will make fluorescently labelled DNA and RNA constructs and we will use them to investigate the physical structures of genes (including gene loops) and to understand the dynamics of long-range interactions in chromatin, part of the structure of a chromosome, by super resolution microscopy. This will allow us to understand the relationship between the tight packaging of DNA in cells and its ability to regulate the synthesis of proteins. We will prepare fluorescently labelled RNA substrates to investigate mechanisms used by the influenza virus to make proteins and to replicate (copy) itself: theses phenomena will be studied by single-molecule FRET (a very sensitive technique for measuring distances between two fluorescent labels) and super-resolution imaging. This will help us to understand the biology of RNA viruses, an important step towards developing improved therapies. We will use click ligation to build artificial molecular machines that will be designed to carry out unique sets of chemical reactions in a precisely controlled manner. This technology may lead to new ways to develop biologically active compounds including drugs. An internationally-leading team from Southampton and Oxford has been assembled and extensive preliminary studies have been carried out to prove feasibility.
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