rRNA processing (Homo sapiens)
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Description
Each eukaryotic cytosolic ribosome contains 4 molecules of RNA: 28S rRNA (25S rRNA in yeast), 5.8S rRNA, and 5S rRNA in the 60S subunit and 18S rRNA in the 40S subunit. The 18S rRNA, 5.8S rRNA, and 28S rRNA are produced by endonucleolytic and exonucleolytic processing of a single 47S precursor (pre-rRNA) (reviewed in Henras et al. 2015). Transcription of ribosomal RNA genes, processing of pre-rRNA, and assembly of precursor 60S and 40S subunits occurs in the nucleolus (reviewed in Hernandez-Verdun et al. 2010). Within the nucleolus non-transcribed DNA and inactive polymerase complexes are located in the fibrillar center, active DNA polymerase I transcription occurs at the interface between the fibrillar center and the dense fibrillar component, early processing of pre-rRNA occurs in the dense fibrillar component, and late processing of pre-rRNA occurs in the granular component (Stanek et al. 2001).
Processed ribosomal RNA contains many modified nucleotides which are generated by enzymes acting on encoded nucleotides contained in the precursor rRNA (reviewed in Boschi-Muller and Motorin et al.2013). The most numerous modifications are pseudouridine residues and 2'-O-methylribonucleotides. Pseudouridylation is guided by base pairing between the precursor rRNA and a small nucleolar RNA (snoRNA) in a Box C/D snoRNP (reviewed in Henras et al 2004, Yu and Meier 2014). Similarly, 2'-O-methylation is guided by base pairing between the precursor rRNA and a snoRNA in a Box H/ACA snoRNP (reviewed in Henras et al. 2004, Hamma and Ferre-D'Amare 2010). Other modifications include N(1)-methylpseudouridine, 5-methylcytosine, 7-methylguanosine, 6-dimethyladenosine, and 4-acetylcytidine. Modification of nucleotides occur as the pre-rRNA is being cleaved. However, the order of cleavage and modification steps is not clear so these two processes are presented separately here. Defects in ribosome biogenesis factors can cause disease (reviewed in Freed et al. 2010) View original pathway at:Reactome.
Processed ribosomal RNA contains many modified nucleotides which are generated by enzymes acting on encoded nucleotides contained in the precursor rRNA (reviewed in Boschi-Muller and Motorin et al.2013). The most numerous modifications are pseudouridine residues and 2'-O-methylribonucleotides. Pseudouridylation is guided by base pairing between the precursor rRNA and a small nucleolar RNA (snoRNA) in a Box C/D snoRNP (reviewed in Henras et al 2004, Yu and Meier 2014). Similarly, 2'-O-methylation is guided by base pairing between the precursor rRNA and a snoRNA in a Box H/ACA snoRNP (reviewed in Henras et al. 2004, Hamma and Ferre-D'Amare 2010). Other modifications include N(1)-methylpseudouridine, 5-methylcytosine, 7-methylguanosine, 6-dimethyladenosine, and 4-acetylcytidine. Modification of nucleotides occur as the pre-rRNA is being cleaved. However, the order of cleavage and modification steps is not clear so these two processes are presented separately here. Defects in ribosome biogenesis factors can cause disease (reviewed in Freed et al. 2010) View original pathway at:Reactome.
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rRNA processing in
the nucleolusFollowing cleavage of the pre-rRNA within internal transcribed spacer 1 (ITS1), the pre-ribosomal particle separates into a pre-60S subunit and a pre-40S subunit in the nucleolus (reviewed in Hernandez-Verdun et al. 2010, Phipps et al. 2011). The pre-60S and pre-40S ribosomal particles are then exported from the nucleus to the cytoplasm where the processing factors dissociate and recycle back to the nucleus
Nuclease digestions of the 47S pre-rRNA can follow several paths. In the major pathway, the ends of the 47S pre-rRNA are trimmed to yield the 45S pre-rRNA. Digestion at site 2 (also called site 2b in mouse, see Henras et al. 2015 for nomenclature) cleaves the 45S pre-rRNA to yield the 30S pre-rRNA containing the 18S rRNA of the small subunit and the 32S pre-rRNA containing the 5.8S rRNA and the 28S rRNA of the large subunit. The 32S pre-rRNA is digested in the nucleus to yield the 5.8S rRNA and the 28S rRNA while the 30S pre-rRNA is digested in the nucleus to yield the 18SE pre-rRNA which is then processed in the nucleus and cytosol to yield the 18S rRNA. At least 286 human proteins, 74 of which have no yeast homolog, are required for efficient processing of pre-rRNA in the nucleus (Tafforeau et al. 2013)
Annotated Interactions
Mitochondrial RNase P, comprising 3 protein subunits and no RNA moiety (Holzmann et al. 2008), endonucleolytically cleaves polycistronic mitochondrial transcripts at the 5' ends of the tRNA sequences (Sanchez et al. 2011, Howard et al. 2012, Vilardo et al. 2012, Li et al. 2015, Reinhard et al. 2015, Vilardo and Rossmanith 2015). A subcomplex of RNase P also functions as a tRNA methyltransferase and the SDR5C1 subunit is an amino acid and fatty acid dehydrogenase. Mutations in the SDR5C1 subunit of RNase P cause HSD10 disease, which is characterized by progressive neurodegeneration and cardiomyopathy (Vilardo and Rossmanith 2015)
ELAC2 cleaves polycistronic mitochondrial transcripts at the 3' ends of the tRNA sequences (Brzezniak et al. 2011, Sanchez et al. 2011). Different isoforms of ELAC2 are present in the nucleus and mitochondria (Rossmanith 2011). Mutations in ELAC2 cause cardiac hypertrophy (Haack et al. 2013) and disorders of oxidative phosphorylation (reviewed in Van Haute et al. 2015).
Unknown nucleases also cleave the H strand transcript at sites 5' to MT-CO3, 5' to MT-CO1, and 5' to MT-CYB (reviewed in Van Haute et al. 2015).