The CMR complex for prokaryotic RNA silencing

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The battle between viruses and cells is brutal and often compared to an "Arms Race". It is the most ancient of wars - as old as life itself. Viral infections cause millions of human casualties globally every year. The extreme evolutionary pressure exerted on cells by viruses, and vice versa, has been and remains a key driving force in evolution. For humankind, there are clear imperatives to explore the possibilities of virus-mediated cell killing for pathogenic bacteria and, conversely, to harness bacterial virus immunity systems in nature to the benefit of food production. Arguably, most exciting discovery in prokaryotic molecular biology in the past 5-10 years is the CRISPR system. CRISPRs are DNA sequences found in the genomes of many bacteria and archaea. They consist of short repeats flanking "spacers" that are often derived from viral sequences. The CRISPR region of the genome is transcribed to make an RNA copy, which is then chopped up to generate individual CRISPR RNA molecules, each with the potential to match the sequence of an invading virus. CRISPR-mediated viral defence (or Interference) is mediated by two large, complex molecular machines, CASCADE and CMR, targetting viral DNA and RNA, respectively. This project is focused on the CMR complex, which is less well understood. We have shown that CMR uses CRISPR RNA to degrade viral RNA targets in a sequence specific reaction. We now wish to understand the molecular basis for this reaction, which is probably unique in prokaryotes. Studies will focus on the active sites of the enzyme that degrades the RNA and the details of the interactions between RNA and protein. Further, we aim to harness the CMR complex to develop sequence dependent RNA silencing in prokaryotes. This technology is not available in a robust form for prokaryotes, unlike in eukaryotes where the RNAi system is used to silence specific genes. If we can develop this technology it will open the door to new possibilities in the manipulation of gene expression in bacteria and archaea with many downstream applications.