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Maturation of pre‐40S particles in yeast and humans

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The synthesis of ribosomal subunits in eukaryotes requires the interplay of numerous maturation and assembly factors (AFs) that intervene in the insertion of ribosomal proteins within pre‐ribosomal particles, the ribosomal subunit precursors, as well as in pre‐ribosomal RNA (rRNA) processing and folding. Here, we review the intricate nuclear and cytoplasmic maturation steps of pre‐40S particles, the precursors to the small ribosomal subunits, in both yeast and human cells, with particular emphasis on the timing and mechanisms of AF association with and dissociation from pre‐40S particles and the roles of these AFs in the maturation process. We highlight the particularly complex pre‐rRNA processing pathway in human cells, compared to yeast, to generate the mature 18S rRNA. We discuss the information gained from the recently published cryo‐electron microscopy atomic models of yeast and human pre‐40S particles, as well as the checkpoint/quality control systems that seem to operate to probe functional sites within yeast cytoplasmic pre‐40S particles. This article is categorized under: RNA Processing > rRNA Processing Translation > Ribosome Biogenesis
Maturation pathway of pre‐40S particles in Saccharomyces cerevisiae. The nucleolar 90S particle is schematized in green with the components of the small subunit processome in dark green. The possible stages of assembly factor (AF) association with and dissociation from pre‐40S particles are indicated by arrows. The positioning of these AFs on the particles is very approximate, especially in the case of Prp43p, whose exact position on the particles is not known because it is absent from cryo‐electron microscopy structures of pre‐40S particles reported so far. Prp43p is present in nuclear pre‐40S particles, but whether it accompanies them to the cytoplasm is not clear, hence Prp43p has not been positioned on cytoplasmic pre‐40S particles. The dissociation stage of Hrr25p and Rio2p remains unclear (highlighted by a question mark). 80S‐like particles refer to complexes formed by binding of a 60S ribosomal subunit (assumed to be a mature one, although this has not been firmly established) to a cytoplasmic pre‐40S particle. Not schematized is the acquisition by early 80S‐like particles of the so‐called rotated state, characterized by rotation (hence the name) of the body of the small subunit relative to the large subunit and swiveling of the small subunit head. This rotated state is induced and/or stabilized by Fap7p binding and promotes Dim1p dissociation. Final cleavage at the 3′ end of 18S rRNA sequence (D site) performed by the endonuclease Nob1p could occur in late 80S‐like particles (the favored scenario illustrated on the figure) or after dissociation of the late pre‐40S particle from the 60S subunit. The proposed requirement of Pno1p/Dim2p dissociation to allow D‐site cleavage by Nob1p is schematized. For more details, see Section 2 of the main text
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Structure of a human cytoplasmic pre‐40S particle. (a) Solvent (left panel) and 60S interface (right panel) views of the cryo‐electron microscopy (EM)‐derived atomic model of the “state C” pre‐40S particle purified using PNO1/DIM2 as bait (Ameismeier et al., ). The atomic model (pdb code: 6g18) is displayed by ribbons, while the cryo‐EM envelope (EMDB accession code: 4337) is figured by a transparent/gray contour. AFs are color‐coded as indicated on the figure. Ribosomal proteins are represented in pale blue, 18S ribosomal RNA (rRNA) in gray with the ITS1 shown in dark violet and indicated by arrows. Characteristic features of the mature 40S subunit (head: beak; body: platform, left and right feet) are indicated. (b) Molecular details of the PNO1/DIM2‐NOB1‐pre‐18S interactions. The right panel illustrates how the NOB1 active site is positioned 30 Å away from 18S rRNA 3′ end, precluding its cleavage (Ameismeier et al., ). For more details, see Section 3.3 of the main text
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Maturation pathway of pre‐40S particles in humans. The possible stages of assembly factor (AF) association with and dissociation from pre‐40S particles are indicated by arrows. Question marks highlight the fact that the indicated AF association or dissociation stages remain very hypothetical. Note in particular that it is not clearly established when RRP12 associates with and dissociates from pre‐40S particles. Unlike the situation in Saccharomyces cerevisiae, no 80S‐like particle formation has been reported so far in humans. For more details, see Section 3.2 of the main text
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Pre‐ribosomal RNA (rRNA) processing steps leading to human 18S rRNA production. The 47S primary transcript is schematized with the sequences of rRNAs (18S rRNA, gray box; 5.8S and 28S rRNAs, whites boxes) flanked by external (3′ETS, 5′ETS) and internal spacers (ITS1, ITS2). The sites of endonucleolytic cleavages are indicated by thick arrow heads and the intervention of exoribonucleases is schematized by packman cartoons. When known, the names of the endo‐ or exoribonucleases acting at specific steps are indicated. Recent mutagenesis data have shown that hUTP23 with an active PIN domain was required for cleavage at site A0, strongly pointing to hUTP23 as the endonuclease responsible for this cleavage (Wells et al., ). The nuclear membrane is schematized by a broken line. When cleavage of a precursor generates two products, both are depicted (e.g., cleavage of 41S at site E generates 18S‐E and 36S pre‐rRNAs). For more details, see Section 3.1 of the main text
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Structure of early cytoplasmic pre‐40S particles in Saccharomyces cerevisiae. (a) Solvent (left panel) and 60S interface (right panel) views of the cryo‐electron microscopy (EM)‐derived atomic model of a pre‐40S particle purified using a catalytically inactive form of Nob1p as bait (Scaiola et al., ). The atomic model (pdb code: 6FAI) is displayed by ribbons, while the cryo‐EM envelope (EMDB accession code: 4214) is figured by a transparent/gray contour. Assembly factors are color‐coded as indicated on the figure. Ribosomal proteins are represented in pale blue, ribosomal RNA (rRNA) in gray with its 3′ end displayed by black spheres. The following characteristic features of the mature 40S subunit are indicated on the figure: the beak on the head of the particle; the platform, the left and the right foot on the body of the particle. (b) Beak views of the atomic model of the 18S rRNA as found in S. cerevisiae pre‐40S particles (left panel) (pdb accession code: 6FAI) and in the mature 40S subunit (pdb accession code: 4V88). Movements of rRNA helices from the pre‐ to the mature state are indicated by arrows. The rRNA 3′ end, located on the opposite side of the beak, is not indicated on these panels
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RNA Processing > rRNA Processing
Translation > Ribosome Biogenesis

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