The CMR complex for prokaryotic RNA silencing

病毒和细胞之间的战斗是残酷的，经常被比作“军备竞赛”。这是最古老的战争——和生命本身一样古老。病毒感染每年在全球造成数百万人伤亡。病毒对细胞施加的极端进化压力，以及病毒对细胞施加的极端进化压力，一直是并且仍然是进化的关键驱动力。对于人类来说，有明确的必要探索病毒介导的细胞杀死致病菌的可能性，反过来，利用自然界的细菌病毒免疫系统来促进粮食生产。可以说，在过去的5-10年里，原核分子生物学中最令人兴奋的发现是CRISPR系统。crispr是在许多细菌和古生菌的基因组中发现的DNA序列。它们由短重复的侧翼“间隔”组成，通常来自病毒序列。基因组的CRISPR区域被转录成RNA副本，然后被切割成单独的CRISPR RNA分子，每个分子都有可能与入侵病毒的序列相匹配。crispr介导的病毒防御（或干扰）由两个大而复杂的分子机器CASCADE和CMR介导，分别靶向病毒DNA和RNA。这个项目的重点是CMR复合物，这是不太了解。我们已经证明，CMR使用CRISPR RNA在序列特异性反应中降解病毒RNA靶标。我们现在希望了解这种反应的分子基础，这在原核生物中可能是独一无二的。研究将集中在降解RNA的酶的活性位点以及RNA和蛋白质之间相互作用的细节上。此外，我们的目标是利用CMR复合物在原核生物中开发序列依赖的RNA沉默。这种技术并不适用于原核生物，不像在真核生物中，RNAi系统被用来沉默特定的基因。如果我们能够发展这项技术，它将为细菌和古细菌基因表达的操纵打开新的可能性之门，并具有许多下游应用。

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.