Executive Summary : | Ribosomal RNA (rRNA) gene transcription by RNA polymerase I (Pol I) is a major oncogenic feature of cancer. Pol I transcription initiates by assembling transcription factors SL1 and UBTF, and multi-subunit Pol I at the rDNA promoter into a pre-initiation complex (PIC). The activity of PIC components on the rDNA promoter is regulated by pro-survival signaling cascades that promote cell proliferation. Proto-oncogene products like c-MYC, mTOR, and Nucleophosmin interact with PIC components to activate rRNA synthesis, while tumor suppressors like p53, pRb, and PTEN inhibit PIC formation, restraining rRNA synthesis. Hyperactive Pol I transcription could be a crucial aberration favoring malignant transformation. Circular RNAs (circRNAs) have gained interest in molecular oncology, modulating gene expression through altering the functional abundance of miRNAs, lincRNAs, mRNAs, and RNA-binding proteins. Dysregulated expression of circRNAs has been linked to cancer hallmarks, and their cancer-specific expression signatures hold utility as diagnostic, prognostic markers, and therapeutic targets. CircRNAs emanating from genes involved in cancer pathways have shown to promote oncogenesis either by influencing parent gene expression or modulating the activity of other functional molecules. Preliminary studies identified two Pol I subunit-derived circRNAs, circ_0055467 and circ_0056146, significantly upregulated in lung adenocarcinoma (LUAD). The study aims to fully comprehend the functional mechanisms of these circRNAs in LUAD using computational, molecular, and cell biology methods. The mechanistic aspects will be unraveled through RNA-sequencing, knock-in/knockdown studies, and cell-fate assays. |