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Ribosomopathies: how a common root can cause a tree of pathologies.

Danilova N, Gazda HT - Dis Model Mech (2015)

Bottom Line: Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways.The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies.Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA ndanilova@ucla.edu hanna.gazda@childrens.harvard.edu.

No MeSH data available.


Related in: MedlinePlus

A simplified schematic of ribosome biogenesis in human cells. (A) 18S, 5.8S and 28S rRNAs are transcribed by Pol1 in the nucleolus as segments of a long precursor pre-rRNA, which also includes two externally transcribed spacers 5′ETS and 3′ETS and two internally transcribed spacers, ITS1 and ITS2 (B; Box 1). 5S rRNA is transcribed independently by PolIII in the nucleus. (B) Concomitant with transcription, the pre-rRNA assembles with accessory factors and a subset of ribosomal proteins (RPs: RPSs and RPLs). This facilitates the formation of a secondary structure necessary for the correct folding, modification and cleavage of pre-rRNA. (C) After removal of the 5′ETS and cleavage in the ITS1 site, pre-40S (which contains the 20S precursor of 18S rRNA) and pre-60S subunits are formed and continue to mature. 5S rRNA incorporates into pre-60S subunit. Subunits are then exported to the cytoplasm. (D) Once in the cytoplasm, small and large subunits undergo final maturation, which involves the removal of remaining accessory factors and incorporation of missing RPs. (E) A functional ribosome forms after transcribed mRNA binds to the 40S subunit, which triggers association of the 60S subunit with this complex. More than 200 accessory factors, which include helicases, nucleases, small nucleolar RNAs (snoRNAs; Box 1), chaperones and transporters, temporally associate with the maturing ribosomal subunits at various steps. In human cells, pre-rRNA processing is differentially affected by deficiency of various RPs. For example, deficiency of RPS24 or RPS7 prevents formation of the 20S precursor of 18S rRNA, whereas deficiency of RPS19 or RPS17 prevents conversion of the 20S precursor to a mature 18S rRNA.
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DMM020529F2: A simplified schematic of ribosome biogenesis in human cells. (A) 18S, 5.8S and 28S rRNAs are transcribed by Pol1 in the nucleolus as segments of a long precursor pre-rRNA, which also includes two externally transcribed spacers 5′ETS and 3′ETS and two internally transcribed spacers, ITS1 and ITS2 (B; Box 1). 5S rRNA is transcribed independently by PolIII in the nucleus. (B) Concomitant with transcription, the pre-rRNA assembles with accessory factors and a subset of ribosomal proteins (RPs: RPSs and RPLs). This facilitates the formation of a secondary structure necessary for the correct folding, modification and cleavage of pre-rRNA. (C) After removal of the 5′ETS and cleavage in the ITS1 site, pre-40S (which contains the 20S precursor of 18S rRNA) and pre-60S subunits are formed and continue to mature. 5S rRNA incorporates into pre-60S subunit. Subunits are then exported to the cytoplasm. (D) Once in the cytoplasm, small and large subunits undergo final maturation, which involves the removal of remaining accessory factors and incorporation of missing RPs. (E) A functional ribosome forms after transcribed mRNA binds to the 40S subunit, which triggers association of the 60S subunit with this complex. More than 200 accessory factors, which include helicases, nucleases, small nucleolar RNAs (snoRNAs; Box 1), chaperones and transporters, temporally associate with the maturing ribosomal subunits at various steps. In human cells, pre-rRNA processing is differentially affected by deficiency of various RPs. For example, deficiency of RPS24 or RPS7 prevents formation of the 20S precursor of 18S rRNA, whereas deficiency of RPS19 or RPS17 prevents conversion of the 20S precursor to a mature 18S rRNA.

Mentions: The eukaryotic ribosome is composed of a small (40S) and a large (60S) subunit (Kressler et al., 2010). The small subunit includes 18S rRNA and 33 RPs; the large subunit includes 5S rRNA, 28S rRNA, 5.8S rRNA and 46 RPs. The genes encoding rRNA (rDNA) are found in multiple copies organized into tandem repeats. 18S, 5.8S and 28S rRNAs are transcribed as a single pre-rRNA transcript by RNA polymerase I in a substructure of the nucleus called the nucleolus. In yeast, the rDNA repeat also encodes the 5S rRNA, which is transcribed in the reverse direction (Henras et al., 2015). In human cells, the 5S rRNA precursor is transcribed from multiple genes in the nucleoplasm by RNA polymerase III (Henras et al., 2015). Then, 5S rRNA migrates to the nucleolus for further processing and incorporation into the pre-60S subunit. The nascent pre-rRNA assembles co-transcriptionally with a subset of RPs and with multiple other factors that facilitate the folding, modification and cleavage of pre-rRNA and the formation of ribosomal subunits (Fig. 2). Pre-rRNA processing can take place co-transcriptionally as well as post-transcriptionally. In yeast, the pre-40S subunit most often is released by cleavage within the internal transcribed spacer 1 (ITS1) before the transcription of the 3′ end of the pre-rRNA is finished. Details of pre-rRNA processing can be found in recent reviews (Henras et al., 2015; Kressler et al., 2010).Fig. 2.


Ribosomopathies: how a common root can cause a tree of pathologies.

Danilova N, Gazda HT - Dis Model Mech (2015)

A simplified schematic of ribosome biogenesis in human cells. (A) 18S, 5.8S and 28S rRNAs are transcribed by Pol1 in the nucleolus as segments of a long precursor pre-rRNA, which also includes two externally transcribed spacers 5′ETS and 3′ETS and two internally transcribed spacers, ITS1 and ITS2 (B; Box 1). 5S rRNA is transcribed independently by PolIII in the nucleus. (B) Concomitant with transcription, the pre-rRNA assembles with accessory factors and a subset of ribosomal proteins (RPs: RPSs and RPLs). This facilitates the formation of a secondary structure necessary for the correct folding, modification and cleavage of pre-rRNA. (C) After removal of the 5′ETS and cleavage in the ITS1 site, pre-40S (which contains the 20S precursor of 18S rRNA) and pre-60S subunits are formed and continue to mature. 5S rRNA incorporates into pre-60S subunit. Subunits are then exported to the cytoplasm. (D) Once in the cytoplasm, small and large subunits undergo final maturation, which involves the removal of remaining accessory factors and incorporation of missing RPs. (E) A functional ribosome forms after transcribed mRNA binds to the 40S subunit, which triggers association of the 60S subunit with this complex. More than 200 accessory factors, which include helicases, nucleases, small nucleolar RNAs (snoRNAs; Box 1), chaperones and transporters, temporally associate with the maturing ribosomal subunits at various steps. In human cells, pre-rRNA processing is differentially affected by deficiency of various RPs. For example, deficiency of RPS24 or RPS7 prevents formation of the 20S precursor of 18S rRNA, whereas deficiency of RPS19 or RPS17 prevents conversion of the 20S precursor to a mature 18S rRNA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4582105&req=5

DMM020529F2: A simplified schematic of ribosome biogenesis in human cells. (A) 18S, 5.8S and 28S rRNAs are transcribed by Pol1 in the nucleolus as segments of a long precursor pre-rRNA, which also includes two externally transcribed spacers 5′ETS and 3′ETS and two internally transcribed spacers, ITS1 and ITS2 (B; Box 1). 5S rRNA is transcribed independently by PolIII in the nucleus. (B) Concomitant with transcription, the pre-rRNA assembles with accessory factors and a subset of ribosomal proteins (RPs: RPSs and RPLs). This facilitates the formation of a secondary structure necessary for the correct folding, modification and cleavage of pre-rRNA. (C) After removal of the 5′ETS and cleavage in the ITS1 site, pre-40S (which contains the 20S precursor of 18S rRNA) and pre-60S subunits are formed and continue to mature. 5S rRNA incorporates into pre-60S subunit. Subunits are then exported to the cytoplasm. (D) Once in the cytoplasm, small and large subunits undergo final maturation, which involves the removal of remaining accessory factors and incorporation of missing RPs. (E) A functional ribosome forms after transcribed mRNA binds to the 40S subunit, which triggers association of the 60S subunit with this complex. More than 200 accessory factors, which include helicases, nucleases, small nucleolar RNAs (snoRNAs; Box 1), chaperones and transporters, temporally associate with the maturing ribosomal subunits at various steps. In human cells, pre-rRNA processing is differentially affected by deficiency of various RPs. For example, deficiency of RPS24 or RPS7 prevents formation of the 20S precursor of 18S rRNA, whereas deficiency of RPS19 or RPS17 prevents conversion of the 20S precursor to a mature 18S rRNA.
Mentions: The eukaryotic ribosome is composed of a small (40S) and a large (60S) subunit (Kressler et al., 2010). The small subunit includes 18S rRNA and 33 RPs; the large subunit includes 5S rRNA, 28S rRNA, 5.8S rRNA and 46 RPs. The genes encoding rRNA (rDNA) are found in multiple copies organized into tandem repeats. 18S, 5.8S and 28S rRNAs are transcribed as a single pre-rRNA transcript by RNA polymerase I in a substructure of the nucleus called the nucleolus. In yeast, the rDNA repeat also encodes the 5S rRNA, which is transcribed in the reverse direction (Henras et al., 2015). In human cells, the 5S rRNA precursor is transcribed from multiple genes in the nucleoplasm by RNA polymerase III (Henras et al., 2015). Then, 5S rRNA migrates to the nucleolus for further processing and incorporation into the pre-60S subunit. The nascent pre-rRNA assembles co-transcriptionally with a subset of RPs and with multiple other factors that facilitate the folding, modification and cleavage of pre-rRNA and the formation of ribosomal subunits (Fig. 2). Pre-rRNA processing can take place co-transcriptionally as well as post-transcriptionally. In yeast, the pre-40S subunit most often is released by cleavage within the internal transcribed spacer 1 (ITS1) before the transcription of the 3′ end of the pre-rRNA is finished. Details of pre-rRNA processing can be found in recent reviews (Henras et al., 2015; Kressler et al., 2010).Fig. 2.

Bottom Line: Phenotypes of ribosomopathies are mediated both by p53-dependent and -independent pathways.The current challenge is to identify differences in response to ribosomal stress that lead to specific tissue defects in various ribosomopathies.Here, we review recent findings in this field, with a particular focus on animal models, and discuss how, in some cases, the different phenotypes of ribosomopathies might arise from differences in the spatiotemporal expression of the affected genes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular, Cell & Developmental Biology, University of California, Los Angeles, CA 90095, USA ndanilova@ucla.edu hanna.gazda@childrens.harvard.edu.

No MeSH data available.


Related in: MedlinePlus