Biogenesis of mRNA-derived telomerase long noncoding RNA

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Project Summary Most RNA molecules transcribed in mammalian cells do not encode for protein sequences. Among these noncoding RNAs (ncRNA) is a vast family of long noncoding RNAs (lncRNAs) that are larger than 200 nt. LncRNAs can modulate cellular protein expression patterns by influencing the transcription of many genes, the post-transcriptional fate of mRNAs and ncRNAs, and the turnover and localization of proteins. Telomerase RNA is a unique class of lncRNA that functions as an integral component of the telomerase ribonucleoprotein complex which maintains genomic stability and cellular immortality in cancer and stem cells. The overarching goal of this project is to understand the mechanism and regulation of a novel mRNA-derived biogenesis of telomerase RNA (lncRNA) in Ustilago maydis, a basidiomycete fungus. Telomerase RNA in Ascomycete yeasts and animals, telomerase RNAs are transcribed by RNA polymerase II and share biogenesis pathways with small nuclear RNA (snRNA) and box H/ACA small nucleolar RNA (snoRNA), respectively. In contrast, telomerase RNAs in ciliates and plants are transcribed by RNA polymerase III. These distinct biogenesis mechanisms employed by these homologous telomerase RNA molecules from different eukaryotic kingdoms or groups provide unparalleled opportunities for understanding the fundamental principles underlying the biogenesis and evolution of the vast varieties of noncoding RNA species in biology. We have recently identified the first Basidiomycete telomerase RNA from U. maydis, a fungal model organism. Animal and yeast TRs are transcribed by RNA polymerase II with a protective cap at the 5’-end. intriguingly, the U. maydis TR lacks a protective 5’ cap and is processed from the 3’-untranslated region of a protein-coding mRNA precursor. In this research program, we will identify determinants in the TR precursor that regulate the biogenesis of the mature U. maydis TR from the protein-coding mRNA. We will also study the function and expression of the protein encoded in the mRNA precursor. Lastly, we will identify telomerase accessory proteins in U. maydis and determine their roles in regulating the U. maydis TR biogenesis. Successful outcomes of these specific aims will provide comprehensive and exciting details needed for understanding the unprecedented mRNA-derived biogenesis mechanism of telomerase lncRNA.