rRNA modification in the mitochondrion (Homo sapiens)

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8, 153, 9, 104, 12, 173, 91, 2, 5-7, 11...3, 9, 10mitochondrionmitochondrial matrix12S rRNAAdoHcyAdoHcy16S rRNAAdoMetMRM1TFB1MFTSJ2AdoMetRNMTL1MTERF4 NSUN4 AdoMetAdoHcy16S rRNA containing2'-O-methylG-1370AdoHcyAdoHcy16S rRNA containing2'-O-methylG-1145MTERF4:NSUN4AdoMet12S rRNA containing6-dimethylA-936,93712S rRNA containing5-methylC-841AdoMet16S rRNA containing2'-O-methylU-13694, 12, 17


Description

Five modified nucleotides have been detected in the 12S rRNA: 5-methylcytidine-841 catalyzed by NSUN4, 6-dimethyladenosine-936 catalyzed by TFB1M, 6-dimethyladenosine-937 catalyzed by TFB1M, 5-methyluridine-429, and 4-methylcytidine-839 (reviewed in Van Haute et al. 2015). Four modified nucleotides have been detected in 16S rRNA: 2'-O-methylguanosine-1145 catalyzed by MRM1, 2'-O-methylguanosine-1370 catalyzed by RNMTL1 (MRM3), 2'-O-methyluridine-1369 catalyzed by FTSJ2 (MRM2), and pseudouridine-1397. 2'-O-methyluridine-1369 and 2'-O-methylguanosone-1370 occur in the A-loop of rRNA which is located at the peptidyl transferase center of the large subunit. Here the modified residues play a role in interaction with the aminoacyl site of tRNA. Knockouts of TFB1M and NSUN4 are lethal in mice and mutations in TFB1M may be related to aminoglycoside-induced deafness (reviewed in Van Haute et al. 2015). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 6793080
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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  1. Bykhovskaya Y, Mengesha E, Wang D, Yang H, Estivill X, Shohat M, Fischel-Ghodsian N.; ''Human mitochondrial transcription factor B1 as a modifier gene for hearing loss associated with the mitochondrial A1555G mutation.''; PubMed Europe PMC Scholia
  2. Cotney J, McKay SE, Shadel GS.; ''Elucidation of separate, but collaborative functions of the rRNA methyltransferase-related human mitochondrial transcription factors B1 and B2 in mitochondrial biogenesis reveals new insight into maternally inherited deafness.''; PubMed Europe PMC Scholia
  3. Lee KW, Okot-Kotber C, LaComb JF, Bogenhagen DF.; ''Mitochondrial ribosomal RNA (rRNA) methyltransferase family members are positioned to modify nascent rRNA in foci near the mitochondrial DNA nucleoid.''; PubMed Europe PMC Scholia
  4. Spåhr H, Habermann B, Gustafsson CM, Larsson NG, Hallberg BM.; ''Structure of the human MTERF4-NSUN4 protein complex that regulates mitochondrial ribosome biogenesis.''; PubMed Europe PMC Scholia
  5. Guja KE, Venkataraman K, Yakubovskaya E, Shi H, Mejia E, Hambardjieva E, Karzai AW, Garcia-Diaz M.; ''Structural basis for S-adenosylmethionine binding and methyltransferase activity by mitochondrial transcription factor B1.''; PubMed Europe PMC Scholia
  6. Surovtseva YV, Shadel GS.; ''Transcription-independent role for human mitochondrial RNA polymerase in mitochondrial ribosome biogenesis.''; PubMed Europe PMC Scholia
  7. McCulloch V, Seidel-Rogol BL, Shadel GS.; ''A human mitochondrial transcription factor is related to RNA adenine methyltransferases and binds S-adenosylmethionine.''; PubMed Europe PMC Scholia
  8. Rorbach J, Minczuk M.; ''The post-transcriptional life of mammalian mitochondrial RNA.''; PubMed Europe PMC Scholia
  9. Lee KW, Bogenhagen DF.; ''Assignment of 2'-O-methyltransferases to modification sites on the mammalian mitochondrial large subunit 16 S ribosomal RNA (rRNA).''; PubMed Europe PMC Scholia
  10. Rorbach J, Boesch P, Gammage PA, Nicholls TJ, Pearce SF, Patel D, Hauser A, Perocchi F, Minczuk M.; ''MRM2 and MRM3 are involved in biogenesis of the large subunit of the mitochondrial ribosome.''; PubMed Europe PMC Scholia
  11. Metodiev MD, Lesko N, Park CB, Cámara Y, Shi Y, Wibom R, Hultenby K, Gustafsson CM, Larsson NG.; ''Methylation of 12S rRNA is necessary for in vivo stability of the small subunit of the mammalian mitochondrial ribosome.''; PubMed Europe PMC Scholia
  12. Yakubovskaya E, Guja KE, Mejia E, Castano S, Hambardjieva E, Choi WS, Garcia-Diaz M.; ''Structure of the essential MTERF4:NSUN4 protein complex reveals how an MTERF protein collaborates to facilitate rRNA modification.''; PubMed Europe PMC Scholia
  13. Raimundo N, Song L, Shutt TE, McKay SE, Cotney J, Guan MX, Gilliland TC, Hohuan D, Santos-Sacchi J, Shadel GS.; ''Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness.''; PubMed Europe PMC Scholia
  14. Lee S, Rose S, Metodiev MD, Becker L, Vernaleken A, Klopstock T, Gailus-Durner V, Fuchs H, Hrabě De Angelis M, Douthwaite S, Larsson NG.; ''Overexpression of the mitochondrial methyltransferase TFB1M in the mouse does not impact mitoribosomal methylation status or hearing.''; PubMed Europe PMC Scholia
  15. Van Haute L, Pearce SF, Powell CA, D'Souza AR, Nicholls TJ, Minczuk M.; ''Mitochondrial transcript maturation and its disorders.''; PubMed Europe PMC Scholia
  16. Seidel-Rogol BL, McCulloch V, Shadel GS.; ''Human mitochondrial transcription factor B1 methylates ribosomal RNA at a conserved stem-loop.''; PubMed Europe PMC Scholia
  17. Cámara Y, Asin-Cayuela J, Park CB, Metodiev MD, Shi Y, Ruzzenente B, Kukat C, Habermann B, Wibom R, Hultenby K, Franz T, Erdjument-Bromage H, Tempst P, Hallberg BM, Gustafsson CM, Larsson NG.; ''MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
114861view16:36, 25 January 2021ReactomeTeamReactome version 75
113307view11:37, 2 November 2020ReactomeTeamReactome version 74
112518view15:47, 9 October 2020ReactomeTeamReactome version 73
101430view11:30, 1 November 2018ReactomeTeamreactome version 66
100968view21:08, 31 October 2018ReactomeTeamreactome version 65
100505view19:42, 31 October 2018ReactomeTeamreactome version 64
100051view16:25, 31 October 2018ReactomeTeamreactome version 63
99603view14:59, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99217view12:44, 31 October 2018ReactomeTeamreactome version 62
93533view11:26, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
12S rRNA containing 5-methylC-841RnaENST00000389680 (Ensembl)
12S rRNA containing 6-dimethylA-936,937RnaENST00000389680 (Ensembl)
12S rRNARnaENST00000389680 (Ensembl)
16S rRNA containing 2'-O-methylG-1145RnaENST00000387347 (Ensembl)
16S rRNA containing 2'-O-methylG-1370RnaENST00000387347 (Ensembl)
16S rRNA containing 2'-O-methylU-1369RnaENST00000387347 (Ensembl)
16S rRNARnaENST00000387347 (Ensembl)
AdoHcyMetaboliteCHEBI:16680 (ChEBI)
AdoMetMetaboliteCHEBI:15414 (ChEBI)
FTSJ2ProteinQ9UI43 (Uniprot-TrEMBL)
MRM1ProteinQ6IN84 (Uniprot-TrEMBL)
MTERF4 ProteinQ7Z6M4 (Uniprot-TrEMBL)
MTERF4:NSUN4ComplexR-HSA-6793090 (Reactome)
NSUN4 ProteinQ96CB9 (Uniprot-TrEMBL)
RNMTL1ProteinQ9HC36 (Uniprot-TrEMBL)
TFB1MProteinQ8WVM0 (Uniprot-TrEMBL)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
12S rRNA containing 5-methylC-841ArrowR-HSA-6793057 (Reactome)
12S rRNA containing 6-dimethylA-936,937ArrowR-HSA-6793066 (Reactome)
12S rRNAR-HSA-6793057 (Reactome)
12S rRNAR-HSA-6793066 (Reactome)
16S rRNA containing 2'-O-methylG-1145ArrowR-HSA-6793122 (Reactome)
16S rRNA containing 2'-O-methylG-1370ArrowR-HSA-6793096 (Reactome)
16S rRNA containing 2'-O-methylU-1369ArrowR-HSA-6793127 (Reactome)
16S rRNAR-HSA-6793096 (Reactome)
16S rRNAR-HSA-6793122 (Reactome)
16S rRNAR-HSA-6793127 (Reactome)
AdoHcyArrowR-HSA-6793057 (Reactome)
AdoHcyArrowR-HSA-6793066 (Reactome)
AdoHcyArrowR-HSA-6793096 (Reactome)
AdoHcyArrowR-HSA-6793122 (Reactome)
AdoHcyArrowR-HSA-6793127 (Reactome)
AdoMetR-HSA-6793057 (Reactome)
AdoMetR-HSA-6793066 (Reactome)
AdoMetR-HSA-6793096 (Reactome)
AdoMetR-HSA-6793122 (Reactome)
AdoMetR-HSA-6793127 (Reactome)
FTSJ2mim-catalysisR-HSA-6793127 (Reactome)
MRM1mim-catalysisR-HSA-6793122 (Reactome)
MTERF4:NSUN4mim-catalysisR-HSA-6793057 (Reactome)
R-HSA-6793057 (Reactome) MTERF4 forms a complex with NSUN4 (Camara et al. 2011, Spahr et al. 2012, Yakubovskaya et al. 2012) and recruits NSUN4 to the ribosome where NSUN4 transfers a methyl group from S-adenosylmethionine to the 5 position of cytidine-841 in 12S rRNA (Camara et al. 2011). Knockout of MTERF4 in mice is lethal and cardiomyocyte-specific knockout is accompanied by mitochondrial cardiomyopathy (Camara et al. 2011).
R-HSA-6793066 (Reactome) TFB1M transfers methyl groups from S-adenosylmethionine to the 6 position of adenosine residues at nucleotides 936 and 937 in 12S mitochondrial rRNA (McCulloch et al. 2002, Seidel-Rogol et al. 2003, Cotney et al. 2009, Guja et al. 2013). The mitochondrial RNA polymerase POLRMT associates directly with TFB1M and increases its methylase activity (Surovtseva and Shadel 2013). Alleles of TFB1M modify the severity of hearing loss associated with the A1555G mutation in 12S rRNA (Bykhovskaya et al. 2004). The A1555G mutation may cause hypermethylation of 12S rRNA which activates AMP kinase, E2F1, and apoptosis (Cotney et al. 2009, Raimundo et al. 2012), however the reported hypermethylation and deafness phenotype have been questioned (Lee et al. 2015). Disruption of Tfb1m in mice is lethal and causes loss of adenine methylation of the 12S RNA (Metodiev et al. 2009).
R-HSA-6793096 (Reactome) MRM3 (RNMTL1) associates with the large mitochondrial ribosomal subunit and transfers a methyl group from S-adenosylmethionine to the 2' hydroxyl group of guanosine-1370 of 16S rRNA (Lee et al. 2013, Lee and Bogenhagen 2014). Inactivation of RNMTL1 causes aberrant assembly of large ribosomal subunits, decreased mitochondrial translation, and respiratory incompetence (Rorbach et al. 2014).
R-HSA-6793122 (Reactome) MRM1 located in foci near mitochondrial nucleoids (Lee et al. 2013) transfers a methyl group from S-adenosylmethionine to the 2' hydroxyl of guanosine-1145 in 16S rRNA (Lee and Bogenhagen 2014).
R-HSA-6793127 (Reactome) MRM2 (FTSJ2) located in foci near mitochondrial nucleoids (Lee et al. 2013) transfers a methyl group from S-adenosylmethionine to the 2' hydroxyl of uridine-1369 in 16S rRNA (Lee and Bogenhagen 2014, Rorbach et al. 2014). Inactivation of FTSJ2 causes aberrant assembly of large mitochondrial subunits, reduced mitochondrial translation, and respiratory incompetence (Rorbach et al. 2014).
RNMTL1mim-catalysisR-HSA-6793096 (Reactome)
TFB1Mmim-catalysisR-HSA-6793066 (Reactome)
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