Crosstalk Between Ribosome Synthesis and Cell Cycle Progression and Its Potential Implications in Human Diseases

Abstract

The connections between ribosome synthesis and cell cycle progression have been the focus of numerous studies and two conserved features emerge from the reported data. The first one is that ribosome synthesis is monitored during the G1 phase of the cell cycle through a surveillance mechanism that communicates with and regulates the G1–S transition machinery. In mammalian cells, this mechanism implicates p53 and the current model proposes that in response to defects in ribosome biogenesis, several ribosomal proteins and ribosome synthesis factors inhibit the p53 ubiquitin ligase Mdm2 and thereby stabilize p53, which results in cell cycle arrest in G1 and/or apoptosis. The second emerging feature, the biological significance of which remains unclear, is that several factors involved in ribosome synthesis are also directly required for specific stages of cell cycle progression, in particular S phase or mitosis. In the past decade, mutations in genes encoding ribosome components or ribosome synthesis factors have been associated with several human diseases, collectively referred to as “ribosomopathies,” characterized by recurrent symptoms including hematopoietic defects, developmental anomalies, and cancer predisposition. One current hypothesis is that these symptoms result from impaired proliferation due to p53 activation in response to ribosome synthesis defects.