Nucleolar Organization in Response to Transcriptional Stress

Abstract

The nucleolus, a prominent membrane-less nuclear compartment, is organized around ribosomal RNA (rRNA) gene (rDNA) clusters, known as nucleolar organizing regions (NORs), located on the short arms of acrocentric chromosomes. It serves as the primary site for ribosome biogenesis, an energy-intensive process crucial for cell growth and proliferation. This involves RNA polymerase I (Pol I)-mediated transcription of 47S precursor rRNA (pre-rRNA), pre-rRNA processing, and ribosomal subunit assembly, reflected in its tripartite structure maintained by liquid-liquid phase separation. Recent evidence indicates that only about 30% of nucleolar proteins are exclusively involved in ribosome production. The remaining proteome participates in diverse cellular functions, establishing the nucleolus as a multifunctional organelle. It functions as a critical stress sensor and signaling hub, responding to various intracellular insults such as nutrient starvation, DNA damage, and viral infection. Many chemotherapeutic agents also induce the response called nucleolar stress via disruption of the nucleolar structure or function, potentially leading to rDNA instability. Nucleolar stress frequently leads to dynamic transition of nucleolar proteins, inducing nucleolar reorganization. Of these, the stress induced by transcriptional changes leads to the unique nucleolar structures termed nucleolar caps and nucleolar necklaces. In this review, we summarize the recent findings about the molecular mechanism of nucleolar changes upon stresses and discuss the possible relationship between rDNA instability and cancer.

Keywords: cancer; liquid–liquid phase separation; nucleolus; rDNA stability; transcriptional stress.