研究领域

1) Structure, function and evolution of small RNAs and protein-RNA complexes in protist organisms 2) Evolution of the spliceosome and spliceosomal introns 3) Bioinformatic strategies to identify non-coding RNAs in eukaryotes

The primary research focus in the Russell lab is to elucidate the structure, function and evolution of selected eukaryotic protein-RNA complexes (RNPs). Our strategy employs single-celled eukaryotic microbes (specifically protists) as model systems in which to study cellular processes that are shared with more complex organisms such as humans. One of our long-term objectives is to understand some of the mechanisms of human disease caused by alterations to the structure and function of these macromolecular complexes. Our research is also providing novel insights about the cellular biology of previously unexplored eukaryotic taxa. Our main areas of interest include: RNA Biology and Evolution Small ribonucleic acids are an important class of cellular molecules that regulate gene expression in all organisms. The recent discovery and manipulation of small interfering RNAs (siRNAs) and microRNAs (miRNAs) has revolutionized our understanding of several areas of eukaryotic biology and consequently led to the awarding of the 2006 Nobel Prize for Physiology or Medicine to Andrew Fire and Craig Mello for their pioneering work in the RNAi field. In our lab we are investigating two main classes of small ribonucleic acids, the small nucleolar (sno) RNAs and the small nuclear RNAs (snRNAs). The primary cellular function of snoRNAs is to target the modification of other classes of stable RNAs such as ribosomal RNAs, snRNAs, and transfer RNAs. They are a very ancient class of molecules and homologs of snoRNAs are also found in archaeal organisms (Omer et al., Science, 2000). We still have much to learn about the possible cellular targets and functions for snoRNAs and the recent characterization of a snoRNA that regulates the alternative splicing of a serotonin receptor messenger RNA (Kishore and Stamm, Science, 2006) indicates that many surprises still await. Our lab is identifying and characterizing snoRNAs in different protist species with a particular interest in the organism Euglena gracilis. We are determining the functional targets for these new snoRNAs and we are also establishing in vitro systems to study the structure and mechanism of action of these RNAs and their associated proteins. SnRNAs are small RNAs that are integral components of the spliceosome, the massive protein-RNA complex that mediates the removal of introns from eukaryotic messenger RNAs. Our lab is identifying snRNAs and other spliceosomal components in diverse eukaryotic organisms. We are particularly interested in the snRNAs that are components of the minor spliceosome, the complex that removes an atypical class of spliceosomal introns. By studying both snoRNAs and snRNAs in phylogenetically diverse eukaryotes we are also addressing questions about the evolutionary history of these molecules. Protist Biology Protists make up most of the phylogenetic diversity within eukaryotes and several key biological discoveries were initially made in these organisms. One of the first identified catalytic RNAs (a self-splicing group I intron) (Thomas Cech, Nobel Prize in Chemistry, 1989) and the telomerase RNA-mediated mechanism of eukaryotic chromosome end maintenance were first characterized in the ciliated protozoon Tetrahymena. We are characterizing protein-RNA complexes from several diverse protists including Giardia lamblia, Euglena gracilis, Acanthamoeba castellanii, and several Phytophthora species. Many of these organisms are either animal or plant pathogens. G.lamblia causes human diarrhea ("Beaver fever") and many Phytophthora species are plant pathogens that infect a wide range of agricultural food crops and trees. It is estimated that Phytophthora species cause > 10 billion dollars worth of crop damage per year! Our research is generating new information about the biology of these organisms that may provide new targets and novel strategies for combating their pathogenicity. Intron evolution Introns are intervening sequences that are expressed and subsequently removed from primary RNA transcripts. They most often interrupt the coding regions of genes. Spliceosomal introns are a class of introns found exclusively in eukaryotic organisms and predominantly reside within protein-coding genes. The origin(s) of spliceosomal introns (and of the spliceosome itself) is one of the most hotly debated questions in evolutionary biology. Based on structural and mechanistic similarities, some researchers believe that components of the spliceosome may have evolved from a group II intron. Our lab is identifying and characterizing introns in protists and other unicellular eukaryotes such as fungi. We are examining the conservation of these introns between different eukaryotes, the possible relationships amongst the different intron classes and what these observations may reveal about the age and origin of eukaryotic introns. We are also studying novel intron types, such as the usual class of introns found in Euglenid messenger RNAs, and we are also examining other protist species for the presence of new classes of introns. Genomics and bioinformatics There is a wealth of new genome sequence data available for many protists including some Phytophthora species (Science, Sept. 2006). There are also genome sequencing projects currently underway to characterize representatives of some of the more poorly sampled eukaryotic taxa of evolutionary, economic or medical significance. We are interested in developing new strategies to search for and characterize genes encoding small RNAs in the genomes of these organisms. Our lab is also sequencing the regions of protist genomes where snoRNAs are encoded to learn about snoRNA gene organization and expression. We are also examining these regions for the presence of sequences that may encode novel RNA species. Completely annotating and quantifying the coding capacity of eukaryotic genomes is currently of paramount importance and not a trivial undertaking. Consider for example that the genome of the plant Arabidopsis thaliana is estimated to contain genes encoding > 67,000 unique small RNA species whereas there are only an estimated 27,000 protein-coding genes in this organism.

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Russell AG, Charette JM, Spencer DF, and Gray MW. 2006. An early evolutionary origin for the minor spliceosome. Nature, 443: 863-866. Russell AG, Schnare MN and Gray MW. 2006. A large collection of compact box C/D snoRNAs and their isoforms in Euglena gracilis: Structural, functional and evolutionary insights. Journal of Molecular Biology, 357: 1548-1565. Russell AG, Shutt TE, Watkins RF and Gray MW. 2005. An ancient spliceosomal intron in the ribosomal protein L7a gene (Rpl7a) of Giardia lamblia. BMC Evolutionary Biology, 5: 45. Russell AG, Watanabe Y-i, Charette JM and Gray MW. 2005. Unusual features of fibrillarin cDNA and gene structure in Euglena gracilis: evolutionary conservation of core proteins and structural predictions for methylation-guide box C/D snoRNPs throughout the domain Eucarya. Nucleic Acids Research, 33: 2781-2791. Russell AG, Schnare MN and Gray MW. 2004. Pseudouridine-guide RNAs and other Cbf5p-associated RNAs in Euglena gracilis. RNA, 10: 1034-1046.