RNA Canada ARN Publication Highlight: TTF1 control of LncRNA synthesis delineates a tumor suppressor pathway directly regulating the ribosomal RNA genes, by Dany S. Sibai, Tom Moss and co-workers at Laval University, Quebec City, Quebec
RNA Canada ARN recently spoke with Dany S. Sibai about his recent research article discussing how a long non-coding RNA controls ribosome biogenesis with links to cancer, recently published in the Journal of Cellular Physiology:
Could you summarize your paper for us? We study the cellular mechanisms by which cellular growth and cancer are linked to ribosome biogenesis. In this paper we focus on the tumour suppressor p14/19ARF, which in turn regulates ribosomal RNA (rRNA) synthesis by controlling the nucleolar localization of Transcription Termination Factor 1 (TTF1). Importantly, the role played by TTF1 in regulating the rRNA genes and controlling cellular growth has remained unclear. We show that TTF1 regulates the cell’s ribosome content and hence cell growth by acting as a “roadblock” to the synthesis of a long non-coding RNA (LncRNA) generated from a promoter upstream of the 47S pre-rRNA gene promoter in mouse and human. The endogenous generation of this noncoding RNA does not induce CpG methylation or gene silencing as previously suggested but acts in cis to suppress 47S preinitiation complex formation and hence de novo rRNA synthesis in a mechanism reminiscent of promoter interference or occlusion. Taken together, our data delineate a pathway from the tumor suppressor p14/19ARF to the suppression of cell growth via LncRNA-regulation of ribosome biogenesis.
Why is your paper so cool? What are the important implications? The ubiquitous presence of upstream promoter duplications has been recognized for well over 40 years. However, their functions have remained a mystery. This mystery has in large part been resolved by our demonstration that these promoter duplications act to suppress rRNA synthesis, ribosome biogenesis and cell proliferation in response to p14/p19ARF accumulation and the ejection of TTF1 from the rRNA genes. Thus, we provide a “raison d’être” for the existence of promoter duplications on the rRNA genes. More importantly we reveal the mechanistic link between a key tumour suppressor that is deleted in 40% of human cancers, and the control of cell growth. The mechanism of LncRNA-driven promoter occlusion and its control by TTF1 almost certainly also has broader implications for the dynamic regulation of rRNA gene activity in cell and tissue biology and disease that await future investigations.
Thank you, Dany!
Dr. Sibai and Dr. Moss’s manuscript can be accessed here. Dany Sibai is a recent graduate from the lab of Dr. Tom Moss in the Department of Molecular Biology, Medical Biochemistry and Pathology, the Cancer Research Centre and the Oncology division of RC-CHUQ at Laval University.
Research Gate: Dany Sibai / Tom Moss