New roles for Dicer in the nucleolus and its relevance to cancer

Abstract

The nucleolus is a distinct compartment of the nucleus responsible for ribosome biogenesis. Mis-regulation of nucleolar functions and of the cellular translation machinery has been associated with disease, in particular with many types of cancer. Indeed, many tumor suppressors (p53, Rb, PTEN, PICT1, BRCA1) and proto-oncogenes (MYC, NPM) play a direct role in the nucleolus, and interact with the RNA polymerase I transcription machinery and the nucleolar stress response. We have identified Dicer and the RNA interference pathway as having an essential role in the nucleolus of quiescent Schizosaccharomyces pombe cells, distinct from pericentromeric silencing, by controlling RNA polymerase I release. We propose that this novel function is evolutionarily conserved and may contribute to the tumorigenic pre-disposition of DICER1 mutations in mammals.

Keywords: cancer; dicer; epigenetics; nucleolus; rDNA.

Figure 1.

Overview of nucleolar structure and function. RNA polymerase I transcribes the rDNA repeats at the interface between the fibrillar center (FC) and the dense fibrillar component (DFC). rRNA molecules and ribosomal proteins associate in complexes in the granular component (GC), and are exported outside of the nucleolus as immature ribosomal particles, which are then assembled into ribosomes.

Figure 2.

DICER1 is frequently mutated in cancer. Overview of DICER1 mutations found in several cancer types, as described in and in NCBI ClinVar. The majority of mutations are predicted to be heterozygous germline loss-of-function alleles, while the hotspot for somatic mutations is located at the RNase IIIb domain catalytic residues.