rRNA modification in the nucleus and cytosol (Homo sapiens)

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3-5, 7, 11...24, 406, 8, 10, 22, 26...2, 29, 37, 4822, 23, 41, 439, 13, 38443739cytosolnucleoplasmNOP56 pre-rRNAcontaining2'-O-methylribonucleotides28S rRNA containing5-methylC-4447GAR1 WDR3 21Spre-rRNAcontaining7-methylG-1639,6-dimethylA-1850,1851DHX37 EMG1 AdoHcyFBL Ac-CoATRMT112 DIEXF UTP14A NOC4L Box C/D snoRNA NOP58 UTP18 pre-rRNA containing7-methylG-1639RPS6 Box C/D snoRNPnascent pre-rRNAtranscriptBox H/ACA snoRNA HEATR1 RRP36 AdoHcyDDX47 RPS2 U3 snoRNA AdoHcy18SEpre-rRNAcontaining1-methyl-3-aminocarboxypropylpseudoU-1248IMP4 RPS7 PDCD11 DDX49 Box H/ACA snoRNPDCAF13 pre-rRNA containingpseudouridineNHP2L1 KRR1 FBL NAT10:THUMPD1CIRH1A 18SEpre-rRNAcontaining1-methylpseudoU-1248WDR36 WBSCR22:TRIMT112TSR3UTP6 NHP2L1 AdoMetAdoMetAdoMetRRP7A MTADFCF1 PNO1BMS1 SSU Processomepre-rRNAPiNOP56 UTP14C UTP11L NHP2 NOP14 WDR75 RPS9 NAT10 WDR43 NOL6 18SEpre-rRNAcontaining4-acetylcytidine-1377,1842NOL11 UTP15 IMP3 AdoHcyMPHOSPH10 NOP2TBL3 UTP3 RRP9 UTP20 DDX52 THUMPD1 ATPRPS14 DIMT1NOP10 PWP2 AdoMetDKC1 WDR46 WBSCR22 ADPRCL1 18SEpre-rRNAcontaining1-methylpseudoU-1248AdoMetNOP58 CoA-SH12, 15-17, 19...154437228, 10, 27, 33, 4237374021, 2512237


Description

Human ribosomal RNAs (rRNAs) contain about 200 residues that are enzymatically modified after transcription in the nucleolus (Maden and Khan 1977, Maden 1988, Maden and Hughes 1997, reviewed in Hernandez-Verdun et al. 2010, Boschi-Muller and Motorin 2013). The modified residues occur in regions of the rRNAs that are located in functionally important parts of the ribosome, notably in the A and P peptidyl transfer sites, the polypeptide exit tunnel, and intersubunit contacts (Polikanov et al. 2015, reviewed in Decatur and Fournier 2002, Chow et al. 2007, Sharma and Lafontaine 2015). The two most common modifications are pseudouridines and 2'-O-methylribonucleotides. Formation of pseudouridine from encoded uridine is catalyzed by box H/ACA small nucleolar ribonucleoprotein (snoRNP) complexes (reviewed in Hamma and Ferre-D'Amare 2010, Watkins and Bohnsack 2011, Ge and Yu 2013, Kierzek et al. 2014, Yu and Meier 2014) and methylation of the hydroxyl group of the 2' carbon is catalyzed by box C/D snoRNPs (Kiss-Laszlo et al. 1996, Lapinaite et al. 2013, reviewed in Watkins and Bohnsack 2011). The snoRNP complexes contain common sets of protein subunits and unique snoRNAs that guide each complex to its target nucleotide of the rRNA by base-pairing between the snoRNA and the rRNA (reviewed in Henras et al. 2004, Watkins and Bohnsack 2011). Other modifications of rRNA include 5-methylcytidine (reviewed in Squires and Preiss 2010), 1-methylpseudouridine, 7-methylguanosine, 6-dimethyladenosine, and 4-acetylcytidine (reviewed in Sharma and Lafontaine 2015). In yeast most modifications are introduced co-transcriptionally (Kos and Tollervey 2010, reviewed in Turowski and Tollervey 2015), however the order of modification events and pre-rRNA cleavage events is not well characterized. View original pathway at Reactome.

Comments

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Pathway is converted from Reactome ID: 6790901
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114950view16:47, 25 January 2021ReactomeTeamReactome version 75
113394view11:46, 2 November 2020ReactomeTeamReactome version 74
112599view15:57, 9 October 2020ReactomeTeamReactome version 73
101515view11:37, 1 November 2018ReactomeTeamreactome version 66
101051view21:19, 31 October 2018ReactomeTeamreactome version 65
100582view19:53, 31 October 2018ReactomeTeamreactome version 64
100131view16:38, 31 October 2018ReactomeTeamreactome version 63
99681view15:08, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
94497view09:03, 14 September 2017Mkutmonreactome version 61
86675view09:23, 11 July 2016ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
18SE

pre-rRNA containing

1-methyl-3-aminocarboxypropylpseudoU-1248
R-HSA-8868777 (Reactome)
18SE

pre-rRNA containing

1-methylpseudoU-1248
R-HSA-6790887 (Reactome)
18SE

pre-rRNA containing

1-methylpseudoU-1248
R-HSA-8868782 (Reactome)
18SE

pre-rRNA containing

4-acetylcytidine-1377,1842
R-HSA-6790985 (Reactome)
21S

pre-rRNA containing 7-methylG-1639,

6-dimethylA-1850,1851
R-HSA-6791006 (Reactome) 7-methylguanosine-1639, 6-dimethyladenosine-1850, and 6-dimethyladenosine-1851 refer to the coordinates of the mature 18S rRNA.
28S rRNA containing 5-methylC-4447RnaM11167 (EMBL)
ADPMetaboliteCHEBI:456216 (ChEBI)
ATPMetaboliteCHEBI:30616 (ChEBI)
Ac-CoAMetaboliteCHEBI:15351 (ChEBI)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
BMS1 ProteinQ14692 (Uniprot-TrEMBL)
Box C/D snoRNA R-HSA-6790639 (Reactome)
Box C/D snoRNPComplexR-HSA-6790894 (Reactome)
Box H/ACA snoRNA R-HSA-6790714 (Reactome)
Box H/ACA snoRNPComplexR-HSA-6790885 (Reactome)
CIRH1A ProteinQ969X6 (Uniprot-TrEMBL)
CoA-SHMetaboliteCHEBI:15346 (ChEBI)
DCAF13 ProteinQ9NV06 (Uniprot-TrEMBL)
DDX47 ProteinQ9H0S4 (Uniprot-TrEMBL)
DDX49 ProteinQ9Y6V7 (Uniprot-TrEMBL)
DDX52 ProteinQ9Y2R4 (Uniprot-TrEMBL)
DHX37 ProteinQ8IY37 (Uniprot-TrEMBL)
DIEXF ProteinQ68CQ4 (Uniprot-TrEMBL)
DIMT1ProteinQ9UNQ2 (Uniprot-TrEMBL)
DKC1 ProteinO60832 (Uniprot-TrEMBL)
EMG1 ProteinQ92979 (Uniprot-TrEMBL)
FBL ProteinP22087 (Uniprot-TrEMBL)
FCF1 ProteinQ9Y324 (Uniprot-TrEMBL)
GAR1 ProteinQ9NY12 (Uniprot-TrEMBL)
HEATR1 ProteinQ9H583 (Uniprot-TrEMBL)
IMP3 ProteinQ9NV31 (Uniprot-TrEMBL)
IMP4 ProteinQ96G21 (Uniprot-TrEMBL)
KRR1 ProteinQ13601 (Uniprot-TrEMBL)
MPHOSPH10 ProteinO00566 (Uniprot-TrEMBL)
MTADMetaboliteCHEBI:17509 (ChEBI)
NAT10 ProteinQ9H0A0 (Uniprot-TrEMBL)
NAT10:THUMPD1ComplexR-HSA-6791007 (Reactome)
NHP2 ProteinQ9NX24 (Uniprot-TrEMBL)
NHP2L1 ProteinP55769 (Uniprot-TrEMBL)
NOC4L ProteinQ9BVI4 (Uniprot-TrEMBL)
NOL11 ProteinQ9H8H0 (Uniprot-TrEMBL)
NOL6 ProteinQ9H6R4 (Uniprot-TrEMBL)
NOP10 ProteinQ9NPE3 (Uniprot-TrEMBL)
NOP14 ProteinP78316 (Uniprot-TrEMBL)
NOP2ProteinP46087 (Uniprot-TrEMBL)
NOP56 ProteinO00567 (Uniprot-TrEMBL)
NOP58 ProteinQ9Y2X3 (Uniprot-TrEMBL)
PDCD11 ProteinQ14690 (Uniprot-TrEMBL)
PNO1ProteinQ9NRX1 (Uniprot-TrEMBL)
PWP2 ProteinQ15269 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:43474 (ChEBI)
RCL1 ProteinQ9Y2P8 (Uniprot-TrEMBL)
RPS14 ProteinP62263 (Uniprot-TrEMBL)
RPS2 ProteinP15880 (Uniprot-TrEMBL)
RPS6 ProteinP62753 (Uniprot-TrEMBL)
RPS7 ProteinP62081 (Uniprot-TrEMBL)
RPS9 ProteinP46781 (Uniprot-TrEMBL)
RRP36 ProteinQ96EU6 (Uniprot-TrEMBL)
RRP7A ProteinQ9Y3A4 (Uniprot-TrEMBL)
RRP9 ProteinO43818 (Uniprot-TrEMBL)
SSU ProcessomeComplexR-HSA-6790891 (Reactome)
TBL3 ProteinQ12788 (Uniprot-TrEMBL)
THUMPD1 ProteinQ9NXG2 (Uniprot-TrEMBL)
TRMT112 ProteinQ9UI30 (Uniprot-TrEMBL)
TSR3ProteinQ9UJK0 (Uniprot-TrEMBL)
U3 snoRNA ProteinNR_006880 (NCBI Protein)
UTP11L ProteinQ9Y3A2 (Uniprot-TrEMBL)
UTP14A ProteinQ9BVJ6 (Uniprot-TrEMBL)
UTP14C ProteinQ5TAP6 (Uniprot-TrEMBL)
UTP15 ProteinQ8TED0 (Uniprot-TrEMBL)
UTP18 ProteinQ9Y5J1 (Uniprot-TrEMBL)
UTP20 ProteinO75691 (Uniprot-TrEMBL)
UTP3 ProteinQ9NQZ2 (Uniprot-TrEMBL)
UTP6 ProteinQ9NYH9 (Uniprot-TrEMBL)
WBSCR22 ProteinO43709 (Uniprot-TrEMBL)
WBSCR22:TRIMT112ComplexR-HSA-6790980 (Reactome)
WDR3 ProteinQ9UNX4 (Uniprot-TrEMBL)
WDR36 ProteinQ8NI36 (Uniprot-TrEMBL)
WDR43 ProteinQ15061 (Uniprot-TrEMBL)
WDR46 ProteinO15213 (Uniprot-TrEMBL)
WDR75 ProteinQ8IWA0 (Uniprot-TrEMBL)
nascent pre-rRNA transcriptRnaNR_046235 (NCBI Protein)
pre-rRNA

containing

2'-O-methylribonucleotides
RnaNR_046235 (NCBI Protein)
pre-rRNA containing 7-methylG-1639R-HSA-6790998 (Reactome) 7-methylguanosine-1639 refers to the coordinates of the matue 18S rRNA.
pre-rRNA containing pseudouridineRnaNR_046235 (NCBI Protein)
pre-rRNAR-HSA-8856933 (Reactome) A longer precursor transcript that is processed to yield mature rRNAs. This instance of pre-rRNA has no specified length and is used for annotating reactions in which the precursor is not well characterized.

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
18SE

pre-rRNA containing

1-methyl-3-aminocarboxypropylpseudoU-1248
ArrowR-HSA-8868783 (Reactome)
18SE

pre-rRNA containing

1-methylpseudoU-1248
ArrowR-HSA-6790906 (Reactome)
18SE

pre-rRNA containing

1-methylpseudoU-1248
R-HSA-8868783 (Reactome)
18SE

pre-rRNA containing

4-acetylcytidine-1377,1842
ArrowR-HSA-6790987 (Reactome)
21S

pre-rRNA containing 7-methylG-1639,

6-dimethylA-1850,1851
ArrowR-HSA-6790994 (Reactome)
28S rRNA containing 5-methylC-4447ArrowR-HSA-6790944 (Reactome)
ADPArrowR-HSA-6790987 (Reactome)
ATPR-HSA-6790987 (Reactome)
Ac-CoAR-HSA-6790987 (Reactome)
AdoHcyArrowR-HSA-6790906 (Reactome)
AdoHcyArrowR-HSA-6790907 (Reactome)
AdoHcyArrowR-HSA-6790944 (Reactome)
AdoHcyArrowR-HSA-6790982 (Reactome)
AdoHcyArrowR-HSA-6790994 (Reactome)
AdoMetR-HSA-6790906 (Reactome)
AdoMetR-HSA-6790907 (Reactome)
AdoMetR-HSA-6790944 (Reactome)
AdoMetR-HSA-6790982 (Reactome)
AdoMetR-HSA-6790994 (Reactome)
AdoMetR-HSA-8868783 (Reactome)
Box C/D snoRNPmim-catalysisR-HSA-6790907 (Reactome)
Box H/ACA snoRNPmim-catalysisR-HSA-6790905 (Reactome)
CoA-SHArrowR-HSA-6790987 (Reactome)
DIMT1mim-catalysisR-HSA-6790994 (Reactome)
MTADArrowR-HSA-8868783 (Reactome)
NAT10:THUMPD1mim-catalysisR-HSA-6790987 (Reactome)
NOP2mim-catalysisR-HSA-6790944 (Reactome)
PNO1ArrowR-HSA-6790994 (Reactome)
PiArrowR-HSA-6790987 (Reactome)
R-HSA-6790905 (Reactome) Box H/ACA snoRNP complexes convert uridine to pseudouridine at 97 sites in human 28S, 18S, and 5.8S rRNAs (Kiss et al. 2004, reviewed in Ge and Yu 2013). The box H/ACA snoRNA component guides the complex to specific residues of the rRNAs by base pairing between the regions of the snoRNA and the rRNA (Kiss et al. 2004, Xiao et al. 2009). The human genome encodes more than 80 box H/ACA snoRNAs (Lestrade and Weber 2006).
R-HSA-6790906 (Reactome) EMG1 (NEP1) methylates a pseudouridine residue in precursor rRNA (pre-rRNA) to yield N(1)-methylpseudouridine (Wurm et al. 2010 and inferred from the yeast homolog) in the nucleolus (Eschrich et al. 2002). Following further modification and nucleolytic processing, the N(1)-methylpseduouridine residue will become N1-methyl-N3-(3-amino-3-carboxypropyl) pseudouridine-1248 of the 18S rRNA. A mutation in EMG1 causes Bowen-Conradi Syndrome, which is characterized by growth retardation, microcephaly, severe psychomotor delay, and minor external abnormalities (Armistead et al. 2009). As inferred from the yeast homolog, EMG1 is a component of the small subunit processome (SSU processome) a large complex of proteins that binds the 5' region of pre-rRNA, processes and modifies the 18S rRNA, and assists the assembly of the small ribosomal subunit.
R-HSA-6790907 (Reactome) The Fibrillarin (FBL) component of Box C/D small nucleolar ribonucleoprotein complexes (snoRNPs) transfers a methyl group from s-adenosylmethionine to the 2' hydroxyl group of ribonucleotides in precursor rRNAs (pre-rRNAs) in the nucleolus (Maden and Hughes 1997, inferred from mouse homologs in Cavaille and Bachellerie 1998, and inferred from homologues in Saccharomyces cerevisiae). The box C/D snoRNA component of the complex guides the methylation by base pairing with 10-21 nucleotide regions of the pre-rRNA (Filippova et al. 2015, inferred from mouse homologs in Cavaille and Bachellerie 1998). The protein components of the core box C/D snoRNP are FBL (homologous to NOP1 in yeast), NOP56, NOP58, and NHP2L1 (15.5K, homologous to SNU13 of yeast) (Lyman et al. 1999, Watkins et al. 2000, Watkins et al. 2002, Schultz et al. 2006, McKeegan et al. 2007). More than 100 nucleotide positions in human rRNAs are 2'-O-methylated and the human genome encodes more than 250 box C/D snoRNAs (Lestrade and Weber 2006), which are 50-300 nucleotides in length and contain box C (RUGAGA) and box D (CUGA) elements.
R-HSA-6790944 (Reactome) NOP2 methylates the carbon at the 5th position of the cytosine ring at cytidine-4447 in 28S rRNA (Bourgeois et al. 2015). NOP2 also has a role in rRNA processing that is independent of its methylase activity.
R-HSA-6790982 (Reactome) The WBSCR22:TRMT112 complex, homolog of the Bud23:Trm112 complex in yeast (Ounap et al. 2013), methylates guanosine-1639 of 18S rRNA at the N(7) position of the guanine base (Haag et al. 2015, Zorbas et al. 2015). The WBSCR22:TRMT112 complex but not its methylase activity is required for efficient processing of precursor rRNA at site 2 and site 3 (Haag et al. 2015, Zorbas et al. 2015). Hemizygosity at the region containing WBSCR22 causes Williams-Beuren syndrome (Doll and Grzeschik 2001).
R-HSA-6790987 (Reactome) NAT10 transfers an acetyl group from acetyl coenzyme A to the N4 positions of the residues that will become cytidine 1337 and cytidine-1842 in 18S rRNA (Ito et al. 2014, Sharma et al. 2015). (The point at which NAT10 acts during rRNA nucleolytic processing is unknown.) NAT10 also hydrolyzes ATP, presumably to provide helicase activity for the reaction (Ito et al. 2014, Sharma et al. 2015). NAT10 in a complex with THUMPD1 also acetylates tRNAs, however THUMPD1 is not required for acetylation of rRNA (Sharma et al. 2015).
R-HSA-6790994 (Reactome) DIMT1 (DIMT1L) dimethylates the N(6) position of adenosine-1850 and adenosine-1851 of a precursor to 18S rRNA in the nucleolus (Zorbas et al. 2015). Dimethylation is observed on the 21S precursor and therefore occurs at this stage of rRNA processing or prior. Dimethylation of adenosine residues appears to occur after N(7)-methylation of guanosine-1639 by WBSCR22:TRMT112 (Zorbas et al. 2015). PNO1 is required for the methylation activity of DIMT1 (Zorbas et al. 2015). DIMT1 protein but not DIMT1 methylase activity is also required for efficient concomitant cleavage of 47S precursor rRNA at site A0 and site 1 (Zorbas et al. 2015).
R-HSA-8868783 (Reactome) In the cytoplasm TSR3 transfers an aminocarboxypropyl group from S-adenosylmethionine (AdoMet) to the N(3) position of N(1)-methylpseudouridine at nucleotide 1248 of 18S rRNA yielding N(1)-methyl-N(3)-aminocarboxylpropylpseudouridine-1248 (Meyer et al. 2016). Prior to this reaction, the SNORA13 or ACA13 H/ACA snoRNP (homologue of the snR35 snoRNP in yeast) in the nucleus converts uridine-1248 to pseudouridine-1248 and the EMG1 component of the small subunit processome in the nucleus methylates the N(1) position of pseudouridine-1248. The 18SE precursor of 18S rRNA containing N(1)-methylpseudouridine is then exported to the cytosol as part of the 40S pre-ribosomal subunit. TSR3 is believed to act on the 18SE precursor rather than the mature 18S rRNA because interference with the activity of TSR3 results in an accumulation of 18SE precursor (Meyer et al. 2016).
SSU Processomemim-catalysisR-HSA-6790906 (Reactome)
TSR3mim-catalysisR-HSA-8868783 (Reactome)
WBSCR22:TRIMT112mim-catalysisR-HSA-6790982 (Reactome)
nascent pre-rRNA transcriptR-HSA-6790905 (Reactome)
nascent pre-rRNA transcriptR-HSA-6790907 (Reactome)
nascent pre-rRNA transcriptR-HSA-6790944 (Reactome)
nascent pre-rRNA transcriptR-HSA-6790987 (Reactome)
pre-rRNA

containing

2'-O-methylribonucleotides
ArrowR-HSA-6790907 (Reactome)
pre-rRNA containing 7-methylG-1639ArrowR-HSA-6790982 (Reactome)
pre-rRNA containing 7-methylG-1639R-HSA-6790994 (Reactome)
pre-rRNA containing pseudouridineArrowR-HSA-6790905 (Reactome)
pre-rRNA containing pseudouridineR-HSA-6790906 (Reactome)
pre-rRNAR-HSA-6790982 (Reactome)
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