Area:
Molecular Biology, Genetics, Cell Biology
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High-probability grants
According to our matching algorithm, Richard B. Waring is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
1989 — 1993 |
Waring, Richard |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Three Splice-Site of a Self-Splicing Group I Intron
The ribosomal RNA of Tetrahymena thermophila is produced as a precursor containing an intervening sequence (intron) which is able to catalyze its own excision and to join its flanking sequences (exons). Given the increasingly central role RNA catalysis may play in cell function, it is essential in the long-term to determine the structure of this catalytic RNA and the function of each of its domains. We plan to ask how the intron recognizes the junction between itself and the downstream exon which is known as the 3' splice-site (3'SS). Study of the 3'SS is particularly interesting because the catalytic RNA has to ligate the exons by transesterification while at the same time preventing abortive hydrolysis of the 3'SS. Most other catalytic RNAs simply have to cleave a substrate. It is essential to know both the minimal features required to determine a 3'SS as well as the features required to ensure that only the desired 3'SS is selected. The first aspect will be studied by analyzing mutations deliberately made in the region of the 3'SS. The second will be studied by analyzing the effect of providing various competing 3' splice-sites upstream of the normal 3'SS. A recently discovered cryptic 3'SS and a duplication of the normal 3'SS will be used. By using oligonucleotide directed mutagenesis to make mutations in the normal or the competing 3'SS the features which contribute to 3'SS selection will be identified. Splicing assays will be performed in vitro using synthetically made RNA precursors. A region of the intron that interacts with the upstream splice site has been clearly identified but no such region has been identified for the 3'SS. We will search for it by screening for mutations which only inhibit 3' splicing and by screening for suppressors of mutations which map at the 3'SS. Suppressor mutations which map elsewhere in the intron and restore splicing are likely to lie in regions which interact with the 3'SS. Forward mutations and suppressors can be selected because we have inserted the intron into a gene of E. coli in such a way that the gene is only expressed if the intron splices itself out. The competitive splice-site analysis will also be aided by this in vivo splicing assay.
|
1 |
2002 — 2006 |
Waring, Richard |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Multi-Functional Activities of a Group I Intron-Encoded Protein
The objective of this project is to understand the relationship between two activities of a protein encoded by a group I intron. The protein facilitates a splicing reaction that excises the intron from its precursor RNA and also acts as a DNA endonuclease, cleaving DNA at a specific sequence. It is commonly believed that the RNA splicing activity evolved from a protein that originally functioned solely as a DNA endonuclease. However it is unlikely that this new function arose simply by fusion of an additional gene sequence. Preliminary evidence indicates that the DNA and RNA substrates bind to distinct or partially overlapping sites on the protein. The question then arises as to how a protein acquires a new function and how easily this can be detected. This is particularly relevant to annotating genomes. Attributing a single function to a gene may constitute only partial characterization of the sequence since an unknown number of proteins may "moonlight" and perform a second, unrelated and unforeseen task. Group I introns can catalyze their own excision from RNA precursors. An intron-encoded protein, called a maturase, significantly facilitates removal of such an intron in Aspergillus nidulans. It also has DNA endonuclease activity. The three-dimensional structure of the protein has been obtained with the help of a collaborator and the region which binds the cleavable DNA sequence has been identified. Guided by this model, the relationship between the binding sites of the RNA and DNA substrates will be studied biochemically and genetically. Current diffraction data from crystals of group I introns are of insufficient quality to reveal structural details at the atomic level. Co-crystallizing RNA with a protein can often solve this problem. A collaboration will be performed to obtain a high-resolution structure of the intron-maturase complex. This will not only reveal the RNA binding site on the protein and help to determine how the RNA binding site arose, but also provide a wealth of structural information about the group I intron RNA itself.
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0.915 |