Nucleolus as a cornerstone linking proliferation and metabolism to cellular responses to stress: involvement of transcription factors MYC and p53

Anastasiia Moraleva^*Nadezhda AntipovaPankrat PavlovKira DobrochaevaYury Rubtsov

• Institute of Bioorganic Chemistry (RAS), Moscow, Russia

The nucleoli are a dynamic membraneless organelles in the nucleus playing a key role in cellular homeostasis. Transcription of rDNA, processing of rRNA, and assembly of the ribosomal subunits occur in nucleoli. Aside from ribosome biogenesis, the nucleolus is also involved in the regulation of other crucial functions, including DNA repair, regulation of cell cycle and apoptosis by mediating nucleolar stress responses. This makes it a key hub participating in regulation of various cellular processes. Given the fact, that protein biosynthesis is directly linked to multiple pathways and depends on ribosome production, it is not surprising that ribosome biogenesis is a centerpiece connecting fundamental cellular processes with each other. Of particular interest is the relationship between the nucleolus, cell cycle, and oncogenesis. In tumor and hyperproliferative cells, an increase in nucleolar size and activity directly correlates with enhanced ribosome biogenesis. This process is mutually controlled by oncogenes of the MYC family and tumor suppressors such as p53 and ARF. MYC plays a central role in regulating DNA transcription, and disrupting of ribosome biogenesis regulation could result in nucleolar stress. It induces activation of p53-dependent and p53-independent checkpoint pathways resulting in cell cycle arrest or apoptosis. In addition to its role in carcinogenesis, impaired ribosome biogenesis is associated with neurodegenerative diseases and ribosomopathies such as Diamond–Blackfan anemia. Thus, understanding the molecular mechanisms of nucleolar functions, and its links with main regulators of the cell cycle and oncogenesis is of great importance. It may help finding novel molecular targets and therapeutic approaches to treat disorders associated with dysregulated ribosome biogenesis and control of proliferation. This review considers the main aspects of nucleolar activity regulation, its role in the cell cycle and diseases, and the therapeutic prospects for targeting these processes.