Ribosomal RNAs are produced as lengthy polycistronic precursors containing coding and non-coding sequences, implying that extensive pre-rRNA processing is necessary for the removal of non-coding spacers. Remarkably, this feature is conserved in all three kingdoms of life and pre-rRNA processing has even become more complex during the course of evolution. While the need for such extensive processing remains unclear, it likely offers increased opportunities to finely regulate ribosome synthesis and to temporally and spatially integrate the various components of ribosome synthesis. In this review we discuss our current understanding of pre-rRNA processing pathways in mammals (human and mouse), with a particular focus on the known and putative cleavage sites, and we compare it to budding yeast, the best eukaryotic model, thus far, regarding ribosome synthesis. Based on the emerging research, we suggest that there are likely more pre-rRNA processing sites and alternative processing pathways still to be identified in humans and that a certain level of functional redundancy can be found in the trans-acting factors involved. These features might have been selected because they increase the robustness of pre-rRNA processing by acting as "back-up" mechanisms to ensure the proper maturation of rRNA.
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