| Grant number: | 17/06994-9 |
| Support Opportunities: | Regular Research Grants |
| Start date: | August 01, 2017 |
| End date: | July 31, 2019 |
| Field of knowledge: | Biological Sciences - Biochemistry - Molecular Biology |
| Principal Investigator: | Patricia Pereira Coltri |
| Grantee: | Patricia Pereira Coltri |
| Host Institution: | Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
Abstract
Pre-RNA splicing is an essential step on gene regulation in eukaryotes. The removal of introns and ligation of exons in mature RNA sequences is performed by the spliceosome, a ~2 MDa macromolecular machinery composed of 5 snRNAs (small nuclear RNAs) and more than a hundred proteins. Spliceosome assembly is a dynamic process, and formation of a catalytically competent complex is dependent on rearrangements of many RNA and proteins interactions. Splice site or spliceosome components mutations can lead to several different diseases, including amyotrophic lateral sclerosis, autism and cancer. In this context, spliceosome might have an important therapeutic role. Approximately 35% of microRNAs (miRNAs) are found within the introns in the human genome and have importance on determination of different diseases. Recent mass spectrometry analysis from our research group showed some specific proteins on spliceosomes assembled in introns containing miRNAs 18a and 19a. These miRNAs are part of miR17-92 cluster, which has increased transcription in different types of cancer. Our hypothesis for this proposal is that proteins SF3B4, PPIA1, DDX17, ELAVL1 and hnRNP-G, specifically detected under presence of miR18a and miR19a, could regulate spliceosome activity and miRNAs maturation. In order to test our hypothesis, a series of experiments will be performed to over-express and knock down the expression of these proteins. If our hypothesis holds true, miRNAs transcription and processing state will respond to proteins levels. In addition, a drug that inhibits splicing will be used to test if miRNA maturation can be compromised. If miRNA maturation and function is dependent on splicing, this experiment will show a complete absence of the miRNAs. In a broader context, these results will contribute to understand the mechanisms governing spliceosome regulation and activation, continuing the ongoing laboratory research program. (AU)
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