|
Recent X-ray results in the US have provided a glimpse into the ancient mechanism that helped diversify our genomes. The work not only provides insights into the very earliest forms of life, but could have future applications in gene therapy. It has been said that RNA molecules are the most conformationally and functionally diverse biopolymers on Earth, and they could be the most ancient biomolecules. It comes as no surprise therefore that countless research teams have focused on these materials in the hope of understanding how they form and how they function. In so doing, some hope to unravel the mystery of life itself. Anna Marie Pyle and Navtej Toor of the Department of Molecular Biophysics and Biochemistry, at Yale University, in New Haven, Connecticut, working with Kevin Keating of the Interdepartmental Program in Computational Biology and Bioinformatics at Yale and Sean Taylor of the Department of Molecular, Cellular and Developmental Biology are taking a different tack in their approach to RNA. While many researchers are searching for the specific properties of RNA that allow the molecule to fold into its three-dimensional form, Pyle and colleagues are also wondering how this complex 3D structure is disassembled by cellular metabolism under the guidance of RNA remodelling enzymes and helicases so it can function. The DNA genetic code in so-called higher organisms is used as an indirect template for assembling proteins from amino acids. The go-between is the RNA molecule. However, following transcription from DNA, to RNA, the RNA must be snipped into pieces and then patched together to form the necessary biochemical machinery for stitching together the appropriate amino acids in the right order. This cut & paste job isolates coding sequences of RNA and edits out the intervening sequences, or introns, that are present in the native DNA but are not used in the protein templating. Pyle and her colleagues have spent the best part of sixteen years endeavouring to understand the nature of "group II" introns. This particular type of intron has the distinguishing feature of acting as its own red pen, to stretch the editorial metaphor still further. It catalyses its own deletion from the RNA sequence prior to protein production. Group II introns are ubiquitous in nature, across the plethora of living organisms. Researchers have gleaned a lot of information about their structure and how they function using biochemical and computational analysis, but until now there have been no high-resolution crystal structures available. Pyle and her colleagues have remedied that situation, and the resulting images - of the self-sliced group II intro from Oceanobacillus iheyensis at 3.1 angstrom resolution - provide both confirmation of earlier work as well as new information about the three-dimensional structure of RNA and the mechanism of splicing. "One of the most exciting aspects of this work was that we did not need to do anything disruptive to these molecules to prepare them for structural analysis," explains Pyle, "The molecules showed us their structure, their active site and their activity - all in a natural state. We were even able to visualize their associated ions." Pyle's crystal structure revealed some quite unexpected features of the group II introns. They showed, for instance, that two sections are implicated as key elements of the active site. This finding has thus strengthened the theory that the process of splicing in humans shares a close evolutionary heritage with ancient forms of bacteria. The result thus stretches our biological history back to the earliest times of life on earth. However, the work on Group II introns is not purely about past life and could have future applications in medicine. "Group II introns hold promise in the future as agents of gene therapy," says Pyle, "A free intron is an infectious element that is special because it targets DNA sites very specifically. We hope that further knowledge of these structures may lead to the development of new genetic tools and therapeutics." Related links:
|
|
