Ribosomal RNA (rRNA) genes are transcribed in cells by RNA polymerase I (Pol I) to precursor rRNA. This precursor transcript is subsequently processed into catalytic and structural rRNAs that are essential for ribosome function. Synthesis of rRNA is limiting step for ribosome biogenesis, thus, ultimately determines the growth and proliferative capacities of a cell. rRNA production is a highly regulated process in cells. Deregulated rRNA synthesis has been reported as a cause or consequence of various growth, proliferative and developmental disorders in humans. Importantly, several lines of evidence intimately linked hyperactive rRNA synthesis to uncontrolled cell division, a hallmark feature of cancer. In fact, mutations that result in the aberrant activity of tumour suppressors and/or oncogenes contribute to increased Pol I transcription, suggesting that elevated rRNA synthesis is a prerequisite to oncogenic transformation.
In eukaryotes, rRNA synthesis is fine tuned by multiple mechanisms that include epigenetic modifications, transcriptional activation and pre-rRNA processing. Signalling cascades that influence cell growth and/or proliferation ultimately impinge upon Pol I transcription machinery, thus, dynamically adapting the rate of rRNA synthesis to the metabolic needs of the cell. Despite the progress in understanding the regulation of Pol I transcription, the role(s) of various non-coding RNAs that are involved in the regulation remain totally unexplored.
Non-coding RNAs (ncRNAs) are crucial regulators of gene expression circuits, and are involved in key biological processes such as cell growth and proliferation, cell cycle control, differentiation, apoptosis and tissue development. The regulation of gene expression by ncRNAs has profound impact on human health and disease. Numerous studies have linked erratic expression of ncRNAs such as microRNAs (miRNAs) and long-ncRNAs (lncRNAs) to the aetiology of various diseases, particularly to cancer. Aberrant loss or gain of ncRNAs contributes to initiation, progression, metastasis and drug resistance of a wide spectrum of cancers.
The core interest of our lab is to understand the role of ncRNAs in the regulation of Pol transcription machinery and exploit them for therapeutic targeting of rRNA synthesis.
Role of ncRNAs in the regulation of Pol I transcription
• To identify and elucidate the role of miRNAs and lncRNAs that are involved in the regulation of Pol I transcription. Further, to investigate the molecular mechanism(s) and signalling pathways that are involved in the miRNAs/ lncRNAs–Pol I axis.
• nanotechnology based delivery of thus identified miRNAs or lncRNAs that target Pol I transcription in various in vitro and in vivo cancer models to elucidate functional consequences on cell proliferation and apoptosis.
Functional characterisation of Pol I transcription proteome
• Despite substantial progress in understanding the regulation of Pol I transcription, the comprehensive role(s) of various components and accessory factors of Pol I transcriptional machinery remain unclear. Also, the key regulatory and signalling events that control Pol I transcription under various cellular conditions are yet to be resolved. Therefore, we aim to comprehensively analyse the role of various proteins that are involved, particularly, in the initiation step of Pol I transcription.
Targeting key components of the Pol I transcription machinery for cancer therapy is an emerging paradigm. The recent development of small molecule inhibitors that selectively inhibit Pol I transcription appears to be promising. However, conventional chemotherapy suffers specificity, toxicity and resistance issues. Therefore, novel therapeutics alone or in combination will have enormous clinical significance. The concept of applying ncRNAs as cancer therapeutics is gaining tremendous academic and commercial interest globally. The versatility to target multiple genes or gene networks with minimal toxicity makes ncRNAs a lucrative approach for cancer therapy. Understanding the role of ncRNAs involved in rRNA synthesis regulation will be instrumental for developing ncRNAs-based therapeutics for neoplastic diseases. The outcome of these important, yet elusive, studies will enable to develop novel strategies to treat cancer through targeted downregulation of Pol I transcription with minimal chemotoxicity.