ribosomes and protein synthesis sequence of events

Following transcription, the 47S pre-rRNA is subsequently cleaved and processed into the mature 18S, 5.8S, and 28S rRNA species. This complex in turn recruits the Pol I-specific initiation factor RRN3, which associates with DNA topoisomerase II α (TOPII α) and Pol I to complete assembly of a transcriptionally-competent Pol I complex. SL-1 is composed of the TATA-box-binding protein (TBP) and five Pol I-specific TATA-box-associated factors (TAFs). Pol I transcription initiation involves binding of the upstream binding factor (UBF) to the core promoter region (core) and upstream control element (UCE) of the rDNA promoters and facilitating the recruitment and binding of the selectivity factor 1 (SL-1) complex. RNA Pol I transcribes the ribosomal RNA (rRNA) genes (rDNA) to produce the 47S precursor rRNA (47S pre-rRNA) transcript in the nucleolus. a Ribosome biogenesis is a tightly coordinated process involving all three RNA polymerases (Pol I, Pol II, and Pol III). 10, 13, 14, 15, 16Ī schematic representation of ribosome biogenesis in mammalian cells. This process is exquisitely regulated by multiple signaling pathways in response to growth factors, energy and nutrients that together modulate protein synthesis and thereby cell growth rate and proliferation. Ribosome biogenesis takes place within specialized subnuclear compartments known as the nucleoli 7, 8 and depends on the coordinated regulation of the three DNA-dependent RNA polymerases (Pol I, Pol II, and Pol III), as well as the involvement of a plethora of transcription factors, small nucleolar RNAs (snoRNAs) and non-RPs that cooperatively promote the transcription, modification and processing of rRNAs, synthesis of RPs and ribosome assembly 2, 9, 10, 11, 12 (Fig. Ribosome biogenesis is a highly dynamic and coordinated process, in which ribosomal RNA (rRNA) is synthesized, modified and assembled with RPs to form mature ribosomes. 1 The biosynthesis of ribosomes, the molecular machines that translate messenger RNA (mRNA) into proteins, 2 is a fundamental biological process that is intimately linked to cell growth and proliferation and is considered to be one of the most energy-consuming processes in proliferating mammalian cells.

These biological capabilities are essential characteristics that enable cancer cells to sustain uncontrolled proliferation. Importantly, insights into the mechanisms of resistance to therapies targeting ribosome biogenesis bring new perspectives into the molecular basis of cancer susceptibility in ribosomopathies and new clinical implications for cancer therapy.Ĭell growth and proliferation are two distinct but coupled biological processes that are directly dependent on the tight coordination of protein synthesis and metabolic activity. We also highlight recent advances in ribosome stress-based cancer therapeutics. We particularly discuss the molecular basis of the transition from hypo- to hyper-proliferation in ribosomopathies with elevated cancer risk, a paradox termed “Dameshek’s riddle.” Furthermore, we review the current treatments for ribosomopathies and prospective therapies targeting ribosomal defects. In this article, we review the most recent advances in understanding the molecular consequences of RP mutations and ribosomal defects in ribosomopathies and cancer. Recent discoveries of somatic mutations in RPs in multiple tumor types reinforce the connections between ribosomal defects and cancer. Ribosomopathies are characterized by tissue-specific phenotypic abnormalities and higher cancer risk later in life. Defects in ribosome biogenesis, translation, and the functions of individual RPs, including mutations in RPs have been linked to a diverse range of human congenital disorders termed ribosomopathies. In addition to their canonical ribosomal functions, multiple RPs have extra-ribosomal functions including activation of p53-dependent or p53-independent pathways in response to stress, resulting in cell cycle arrest and apoptosis. The ribosomal proteins (RPs), comprising the structural parts of the ribosome, are essential for ribosome assembly and function.

Ribosome biogenesis and protein synthesis are fundamental rate-limiting steps for cell growth and proliferation.

Ribosomes and protein synthesis sequence of events