Nucleolus as an emerging hub in maintenance of genome stability and cancer pathogenesis

Abstract

The nucleolus is the major site for synthesis of ribosomes, complex molecular machines that are responsible for protein synthesis. A wealth of research over the past 20 years has clearly indicated that both quantitative and qualitative alterations in ribosome biogenesis can drive the malignant phenotype via dysregulation of protein synthesis. However, numerous recent proteomic, genomic, and functional studies have implicated the nucleolus in the regulation of processes that are unrelated to ribosome biogenesis, including DNA-damage response, maintenance of genome stability and its spatial organization, epigenetic regulation, cell-cycle control, stress responses, senescence, global gene expression, as well as assembly or maturation of various ribonucleoprotein particles. In this review, the focus will be on features of rDNA genes, which make them highly vulnerable to DNA damage and intra- and interchromosomal recombination as well as built-in mechanisms that prevent and repair rDNA damage, and how dysregulation of this interplay affects genome-wide DNA stability, gene expression and the balance between euchromatin and heterochromatin. We will also present the most recent insights into how malfunction of these cellular processes may be a central driving force of human malignancies, and propose a promising new therapeutic approach for the treatment of cancer.

A protein-RNA interaction atlas of the ribosome biogenesis factor AATF

“…The known link between ribosome stress and p53 activity in the light of our new data allows for the exciting hypothesis that AATF mediates its effects on cell death employing this pathway. Based on the interaction between r-proteins and the E3 ubiquitin ligase MDM2, defects in ribosome maturation activate p53 19,36,[51][52][53] . Loss of AATF would thus increase p53 activity linking the roles of AATF in ribosome biogenesis and p53 activity.…”

Physical Chemistry of Cellular Liquid‐Phase Separation

“…Although the nucleolus was observed in cells over 100 years ago, only recently have studies demonstrated its liquid‐like properties such as fusion and flowing . The nucleolus is an MLO, best known as the center of ribosome biogenesis, although it has been associated with numerous other roles including ribonucleoprotein formation, genome stability, and cancer . Nucleoli are spatially associated with nucleolar organizer regions on chromosomal DNA, and show dissociation and regrowth during different stages of the cell cycle.…”

“…[27] The nucleolus is an MLO, best knowna st he center of ribosome biogenesis, althoughi th as been associated with numerouso ther roles including ribonucleoprotein formation, genome stability,a nd cancer. [28] Nucleoli are spatially associatedw ithn ucleolar organizer regions on chromosomal DNA, and show dissociation and regrowth during different stages of the cell cycle. Internally,n ucleoli are not spatially uniform and instead show more complex sub-structure.…”

Higher order genomic organization and epigenetic control maintain cellular identity and prevent breast cancer

“…Nucleolar organizer regions (NORs) contain the rRNA genes discussed above are present on five different acrocentric chromosomes are bookmarked during mitosis . This bookmarking provides a basis for the reassembly of these NOR‐bearing chromosomes and biogenesis of nucleoli (Figure ). Interestingly, it was discovered that there is a dominant nucleolus that associates with more of these acrocentric chromosomes.…”

“…Bookmarking of chromatin domains has been proposed to play a significant role in reestablishing fidelity for HCO of the genome . Upon exit from mitosis, the biogenesis of nuclear bodies, which include nucleoli (where ribosomal RNA is transcribed) and histone locus bodies (HLB; where histone mRNA is transcribed), contribute to HCO‐mediated biological control . These physiologically important examples of regulatory compartmentalization are obligatory for the balance between proliferation and cell lineage specificity.…”