Ribosome Biogenesis and Cell Cycle Regulation

Introduction to Ribosome Biogenesis in Cancer Development

Ribosome biogenesis is the process of making ribosomes that occurs both in the cytoplasm and in the nucleolus. Recent studies showed that impaired ribosome biogenesis induces checkpoint control that prevents cell cycle progression. Inhibition of ribosome biogenesis has been shown to block cell proliferation and interfere with cell cycle regulation. There are both p53-dependent and p53-independent mechanisms linking ribosome biogenesis and cell cycle regulation.

P53-dependent Ribosome Biogenesis Inhibition

In most cases, the inhibition of cell proliferation by disturbed ribosome biogenesis is p53-dependent. In p53 wild-type mice, haploinsufficiency of RPL24-uL24 or RPL38-uL38 inhibits ribosome biogenesis and ultimately delays tumor formation and progression. Its mechanism of action is that p21-mediated inhibition of pRb phosphorylation would block the G1/S phase transition and hinder cell proliferation. In addition, activation of the p53/p21/pRb pathway also triggers G2 arrest. In conclusion, the p53 pathway has been recognized as an important mediator of the signaling link between ribosome biogenesis and the cell cycle. Aberrant rRNA processing and ribosome biosynthesis lead to 'nucleolar stress' resulting in cell cycle arrest in a p53-dependent manner.

P53-independent Ribosome Biogenesis Inhibition

There are also p53-independent mechanisms to induce cell cycle arrest during ribosome biogenesis. The POLR1A gene encodes the catalytic subunit of RNA polymerase I. The scientists found that when the POLR1A gene was silenced using a small interfering RNA program, the expression of the transcription factor E2F-1 was down-regulated, which ultimately resulted in the inhibition of rRNA synthesis and cell cycle progression in p53-inactivated cells. This is a novel mechanism that links cell growth to cell proliferation and may help stop the proliferation of p53-deficient cancer cells.

The c-Myc oncoprotein can enhance ribosome biosynthesis and promote cell growth by upregulating RNA polymerase I, II, and III-dependent transcription, and aberrant expression of c-Myc may lead to dysregulated cell growth and tumorigenesis. Ribosomal protein L11 acts as a feedback inhibitor of c-Myc and can control c-Myc function through a negative feedback mechanism. Specifically, L11 binding to Myc box II (MB II) inhibits the recruitment of the coactivator TRRAP and reduces histone H4 acetylation at the promoters of c-Myc target genes.

Fig. 1 POLR1A RNAi selectively inhibits the rRNA synthesis in U2OS and HCT-116 cell lines.¹

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Reference

1. Donati, Giulio, et al. "Selective inhibition of rRNA transcription downregulates E2F-1: a new p53-independent mechanism linking cell growth to cell proliferation." Journal of cell science 124.17 (2011): 3017-3028.