The initiation of mRNA degradation by the direct entry of RNase E and the degradosome with implications for non-nucleolytic gene control

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Many bacterial species pose a significant health-risk to humans, animals and plants, while others are an important source of nutrients and medicines including antimicrobials and anti-cancer agents. Some, including one called Escherichia coli (or E. coli for short), are used as factories for the production of therapeutics and other compounds of commercial or clinical value; much in the same way that yeast can be used to make alcohol. All organisms contain blocks of information called genes, which are passed from one generation to the next. The process by which the information in these genes is manifested in the characteristics of living organisms is called gene expression. The information in a gene is not read directly; instead, a copy called the messenger is made with a limited 'shelf life'. The shelf-life of the messenger determines how many times it can be read and, in turn, the characteristics of an organism. The stability of messengers in E. coli is the subject area of this application. More specifically, we wish to characterise a newly identified mode of recognising messengers that evidence from a number of sources indicates is pivotal to the process of initiating their degradation. We also plan to determine whether this mode of recognition can explain why messengers are highly vulnerable to degradation when they are not being read. This happens, for example, upon the binding of messengers by small RNAs, which represent an emerging class of regulator that is associated with bacterial survival and pathogenicity. In the longer term, our research may also impact the search for new antimicrobials, which is timely given the alarming rate at which resistance to antibiotics is emerging in bacterial populations. The function of E. coli RNase E is essential, so disabling its activity could be lethal to the many pathogens that contain this enzyme. Knocking out RNase E activity after E. coli has grown (in the form of a bio-factory) may also lead to the increased production of compounds of commercial and clinical value, by increasing the number of times the corresponding messengers can be read. This proposal is also relevant to synthetic biology, 'a new and growing science that focuses on re-designing and re-building natural biological systems synthetically from the ground up'. In the 32nd annual Richard Dimbleby lecture, Dr. J. Craig Venter (who is probably best known for heading the private enterprise that sequenced the human genome) outlined how bacteria could be engineered by 'human intelligence' to create renewable energy and combat climate change. This is not science fiction. Modified bacteria are already being used by DuPont to convert sugar into a new polymer that can be used to produce stain-resistant carpets and clothing. Other companies including BP are trying to adapt bacteria to make the next generation of biofuels. Genes with related functions (e.g. those that part of the same pathway or complex) can be expressed as part of the same messenger in bacteria. This ensures that all the components for a particular process are made at the same time. The ultimate goal for synthetic biologists is to be able to design systems from 'scratch' using rules learnt from nature. In these systems, the messengers will need to have a sufficient 'shelf-life' to be able to confer attributes that are desired, while at the same time not being too stable such that the information is permanent. This proposal could provide information necessary for the rational engineering of messengers encoding multiple genes such that different components can be made in different amounts.