Mechanisms of rDNA silencing and the Nucleolar Remodelling Complex (NoRC)

Abstract

Protein synthesis in living cells requires functional ribosomes which are composed of ribosomal proteins and ribosomal RNA (rRNA) molecules. rRNA is transcribed from tandemly repeated ribosomal DNA (rDNA) which is organised into a nuclear compartment termed the nucleolus in S-phase cells. It is essential that rDNA transcription is properly regulated in order to meet the cell's requirements for ribosomes and hence protein synthesis without wasting metabolic energy. In the last twenty years many proteins involved in regulating this process have been identified, suggesting that most organisms contain multiple protein complexes that regulate rDNA packaging and transcription. Importantly, it has become clear that errors in the function of these proteins can permit aberrant cellular growth, including in several classes of cancer. In this review, I discuss the history of how protein complexes such as the Nucleolar Remodelling Complex (NoRC) were discovered, using examples from humans and from model research organisms from different biological groups. I will discuss recent discoveries of the critical roles of rDNA-binding complexes in nucleolar assembly, the widespread occurrence of regulatory non-coding RNAs which interact with these complexes, and the pathways which regulate rDNA transcription in response to cellular energy status. Finally, I will review the growing evidence that misregulation of rDNA transcription not only allows the growth of cancerous cells, but can trigger oncogenesis itself.