MRM2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000027 ribosomal large subunit assembly	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetic inference from PAINT node PTN000100455 (FtsJ/RlmE clade; seeds include E. coli RlmE, fly Mrm2 and human MRM2 itself). Human MRM2 acts specifically in assembly of the mitoribosomal large subunit. Reason: The IBD at PTN000100455 is sound and correctly placed (it spans bacterial RlmE and mitochondrial MRM2, so the generic term is appropriate at the node). For human MRM2, however, the experimental evidence establishes the more specific child term GO:1902775 mitochondrial large ribosomal subunit assembly (is_a GO:0000027), which the gene already carries by IDA/IMP. Human MRM2 appearing in the WITH/FROM list reflects its own experimental grounding, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000100455 SUPPORTS TRANSFER FtsJ/RlmE clade node spanning bacterial RlmE and mitochondrial Mrm2; the generic LSU-assembly term is right at the node, and the mitochondrial child term is the human-specific refinement. UniProtKB:Q9UI43 · human MRM2 SUPPORTS TRANSFER Self-reference is expected, not circular; the target's own experimental annotation is one of the descendant evidences behind the IBD. Proposed replacements: mitochondrial large ribosomal subunit assembly Supporting Evidence: PMID:35177605 In the absence of MRM2, a severe mitochondrial dysfunction phenotype with underlying defects in mitochondrial translation is observed, with the mtLSU being trapped in immature assembly states where domains IV and V of 16S mt-rRNA are unstructured file:human/MRM2/MRM2-uniprot.txt PANTHER; PTHR10920:SF18; RRNA METHYLTRANSFERASE 2, MITOCHONDRIAL; 1.
GO:0000451 rRNA 2'-O-methylation	IDA PMID:34135320 Stepwise maturation of the peptidyl transferase region of hu...	ACCEPT	Summary: Cryo-EM study of human mtLSU assembly intermediates showing that MTERF4-NSUN4 exposes 16S rRNA regions for modification by MRM2. Reason: Only the abstract is cached, but the abstract places MRM2 as the methyltransferase acting on the exposed 16S rRNA region, and the 2'-O-methylation of U1369 by MRM2 is independently established in human cells (PMID:25074936, PMID:25009282, PMID:35177605). Deferring to the curator who read the full text; the claim is core. Supporting Evidence: PMID:34135320 exposes the functionally important regions of rRNA for modification by the MRM2 methyltransferase PMID:35177605 Validation of the catalytic inactivity of the human variants was obtained by RNA LC-MS2, which identified 16S mt-rRNA oligonucleotides containing U3039 solely in its non-methylated state both in MRM2 knock-out cells complemented with MRM2 K59A and MRM2 D154A , as well as in the knock-out background
GO:0000451 rRNA 2'-O-methylation	IMP PMID:32652011 Human GTPBP5 (MTG2) fuels mitoribosome large subunit maturat...	ACCEPT	Summary: GTPBP5 study in which MRM2 siRNA knockdown was used as the reference for fully unmodified Um1369 in RiboMethSeq, showing that MRM2 is required for the Um1369 2'-O-methylation. Reason: The MRM2 knockdown abolishes Um1369 methylation, consistent with the direct enzymatic assignment in PMID:25074936 and the catalytic-mutant data in PMID:35177605. Core process. Supporting Evidence: PMID:32652011 For this reason, the MethScore for Um1369 was converted to real methylation level by using siMRM2 RNA as a reference of totally unmodified RNA. PMID:32652011 MRM2, the methyltransferase that catalyzes the modification of the 16S mt-rRNA A-loop U1369 residue
GO:0000451 rRNA 2'-O-methylation	TAS Reactome:R-HSA-6793127	ACCEPT	Summary: Reactome reaction describing MRM2 methylation of uridine-1369 of 16S rRNA. Reason: Accurate summary of the primary literature (PMID:25074936, PMID:25009282). Core process. Supporting Evidence: Reactome:R-HSA-6793127 MRM2 (FTSJ2) methylates uridine-1369 of 16S rRNA yielding 2'-O-methyluridine PMID:25074936 are responsible for modification of human large subunit rRNA at residues
GO:0005730 nucleolus	IDA PMID:11827451 Identification and characterization of FTSJ2, a novel human ...	REMOVE	Summary: Early (2002) immunofluorescence report placing FTSJ2 in the nucleolus. Reason: Contradicted by all subsequent localisation work. Endogenous MRM2 cofractionates with the mitochondrial matrix marker mtSSB1 and is protected from proteinase K (PMID:25009282), it localises to foci near mtDNA nucleoids (PMID:24036117), and it is recovered on mitoribosomal LSU intermediates by cryo-EM (PMID:34135318). The nucleolar signal is explained by the construct used, an N-terminal GFP fusion that masks the N-terminal mitochondrial transit peptide (UniProt TRANSIT 1..18). No later study supports a nucleolar pool. Supporting Evidence: PMID:24036117 In that report, fusion of GFP on the N terminus of MRM2/FTSJ2 resulted in a nucleolar location. PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005739 mitochondrion	EXP PMID:24036117 Mitochondrial ribosomal RNA (rRNA) methyltransferase family ...	MODIFY	Summary: Imaging and fractionation place MRM2 in mitochondria, in foci near mtDNA nucleoids. Reason: Correct, but the evidence supports the more specific matrix compartment (nucleoids and mitoribosome assembly are in the matrix; fractionation shows matrix-like protease protection). GO:0005759 mitochondrial matrix is already carried by the gene. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:24036117 These proteins are confined to foci located in the vicinity of mtDNA nucleoids.
GO:0005739 mitochondrion	EXP PMID:25009282 MRM2 and MRM3 are involved in biogenesis of the large subuni...	MODIFY	Summary: Endogenous MRM2 cofractionates with mitochondria and is protected from proteinase K, like the matrix marker mtSSB1. Reason: The fractionation result supports the specific matrix location (GO:0005759), which the gene already carries; mitochondrion is correct but less specific than the evidence. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	MODIFY	Summary: High-confidence human mitochondrial proteome (MitoCoP) including MRM2. Reason: Consistent with the targeted studies. The proteome supports organelle-level location only, but the claim about the gene is better expressed as the matrix location established by PMID:25009282 and already carried by the gene. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005739 mitochondrion	IBA GO_REF:0000033	MODIFY	Summary: PAINT inference from node PTN000100456 (eukaryotic mitochondrial Mrm2 clade; seeds mouse Mrm2, yeast Mrm2 and human MRM2). Reason: The node placement is sound and human MRM2 is inside the mitochondrial clade (PTHR10920:SF18). For the human protein the matrix location (GO:0005759) is experimentally supported and already annotated, so the general term is refined rather than kept. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000100456 SUPPORTS TRANSFER Eukaryotic mitochondrial Mrm2 node; human MRM2 is inside the clade (PTHR10920:SF18). Matrix is the refinement supported by human fractionation. UniProtKB:Q9UI43 · human MRM2 SUPPORTS TRANSFER Self-reference is expected, not circular; the target's own experimental annotation is one of the descendant evidences behind the IBD. Proposed replacements: mitochondrial matrix Supporting Evidence: file:human/MRM2/MRM2-uniprot.txt PANTHER; PTHR10920:SF18; RRNA METHYLTRANSFERASE 2, MITOCHONDRIAL; 1. PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005739 mitochondrion	IEA GO_REF:0000120	MODIFY	Summary: Automated location from UniProt subcellular location (curated Mitochondrion) and ARBA. Reason: Correct at organelle level; the curated UniProt location rests on PMID:24036117 and PMID:25009282, which support the more specific matrix term already carried by the gene. Proposed replacements: mitochondrial matrix Supporting Evidence: file:human/MRM2/MRM2-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269\|PubMed:24036117,
GO:0005739 mitochondrion	ISS GO_REF:0000024	MODIFY	Summary: Transfer from mouse Mrm2 (Q9CPY0). Reason: Correct, and redundant with direct human evidence; refined to the matrix location supported in human cells. Proposed replacements: mitochondrial matrix Supporting Evidence: PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005759 mitochondrial matrix	IMP PMID:35177605 A late-stage assembly checkpoint of the human mitochondrial ...	ACCEPT	Summary: MRM2 acts on assembling mtLSU particles and 16S mt-rRNA, which are in the mitochondrial matrix. Reason: MRM2 knock-out traps matrix-resident mtLSU intermediates and abolishes the 16S mt-rRNA modification; together with the protease-protection fractionation (PMID:25009282) this places MRM2 activity in the matrix. Supporting Evidence: PMID:35177605 The human mitochondrial genome is encoded in multiple copies of ~16.6 kb circular double-stranded DNA molecules (mtDNA) present in mitochondrial nucleoids in the mitochondrial matrix. PMID:25009282 Cell fractionation experiments confirmed the mitochondrial localization of the three proteins, as the endogenous proteins cofractionated with the well-characterized mitochondrial matrix protein mtSSB1 and were resistant to proteinase K treatment (Figure 2C).
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-6793127	ACCEPT	Summary: Reactome places the MRM2 reaction in the mitochondrial matrix, near nucleoids. Reason: Consistent with the experimental localisation data. Supporting Evidence: Reactome:R-HSA-6793127 MRM2 (FTSJ2) located in foci near mitochondrial nucleoids (Lee et al. 2013)
GO:0006364 rRNA processing	IMP PMID:35177605 A late-stage assembly checkpoint of the human mitochondrial ...	MODIFY	Summary: MRM2 knock-out and catalytic mutants abolish 2'-O-methylation of U3039 (Um1369) in 16S mt-rRNA. Reason: The experiment shows a specific rRNA modification, rRNA 2'-O-methylation (GO:0000451, a descendant of rRNA processing), which the gene already carries. The broad term adds nothing. Proposed replacements: rRNA 2'-O-methylation Supporting Evidence: PMID:35177605 Validation of the catalytic inactivity of the human variants was obtained by RNA LC-MS2, which identified 16S mt-rRNA oligonucleotides containing U3039 solely in its non-methylated state both in MRM2 knock-out cells complemented with MRM2 K59A and MRM2 D154A , as well as in the knock-out background
GO:0006364 rRNA processing	NAS PMID:11827451 Identification and characterization of FTSJ2, a novel human ...	MODIFY	Summary: Homology-based statement in the original FTSJ2 cloning paper that the protein is likely an RNA methyltransferase involved in RNA processing and modification. Reason: The prediction was borne out, but at the level of a specific modification (rRNA 2'-O-methylation, GO:0000451) established experimentally later. Proposed replacements: rRNA 2'-O-methylation Supporting Evidence: PMID:11827451 FTSJ2 shares significant sequence homology with FtsJ/RrmJ, a recently identified Escherichia coli 23S rRNA uridine-2'-O-methyltransferase. PMID:25074936 are responsible for modification of human large subunit rRNA at residues
GO:0008168 methyltransferase activity	IEA GO_REF:0000002	MODIFY	Summary: InterPro2GO mapping from the FtsJ methyltransferase domain and the RlmE family signature. Reason: Correct but general; the specific activity, rRNA (uridine-2'-O-ribose)-methyltransferase activity (GO:0008650), is experimentally established and already carried by the gene. Proposed replacements: rRNA (uridine-2'-O-ribose)-methyltransferase activity Supporting Evidence: file:human/MRM2/MRM2-uniprot.txt InterPro; IPR015507; rRNA-MeTfrase_E. PMID:35177605 While acting as an assembly factor of the mtLSU, MRM2 is also a S -adenosyl methionine (SAM)-dependent 2′- O -ribose methyltransferase with its target on the 16S mt-rRNA.
GO:0008650 rRNA (uridine-2'-O-ribose)-methyltransferase activity	EXP PMID:25074936 Assignment of 2'-O-methyltransferases to modification sites ...	ACCEPT	Summary: DNAzyme protection assay assigns Um1369 of human 16S mt-rRNA to MRM2. Reason: Direct assignment of the 2'-O-methylated uridine to MRM2 in human cells; corroborated by catalytic-dead mutants (PMID:35177605). Core activity. The cache is abstract-only; the abstract states the conclusion. Supporting Evidence: PMID:25074936 show that MRM1, MRM2, and RNMTL1 are responsible for modification of human large subunit rRNA at residues G(1145), U(1369), and G(1370), respectively.
GO:0008650 rRNA (uridine-2'-O-ribose)-methyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: PAINT inference from PTN000100455, the FtsJ/RlmE clade, seeded by E. coli RlmE, yeast Mrm2 and human MRM2. Reason: The activity is ancestral to the clade (bacterial RlmE methylates the equivalent A-loop uridine of 23S rRNA) and human MRM2 retains the catalytic residues (K59, D154 equivalent to RlmE K38, D124) and the activity experimentally. Human MRM2 in the WITH/FROM list is its own experimental grounding. Supporting Evidence: PMID:35177605 Mutation of the catalytic residues K38 and D124 of Escherichia coli RlmE (equivalent to Homo sapiens MRM2 K59 and D154, respectively) has been shown to abolish its methyltransferase activity file:human/MRM2/MRM2-uniprot.txt HAMAP; MF_01547; RNA_methyltr_E; 1.
GO:0008650 rRNA (uridine-2'-O-ribose)-methyltransferase activity	IEA GO_REF:0000116	ACCEPT	Summary: Rhea mapping from the curated UniProt catalytic activity (uridine(1369) in 16S rRNA 2'-O-methylation). Reason: The Rhea reaction is curated from PMID:25074936 and PMID:35177605 and maps correctly to GO:0008650. Supporting Evidence: file:human/MRM2/MRM2-uniprot.txt S-adenosyl-L-methionine-dependent 2'-O-ribose methyltransferase that catalyzes the formation of 2'-O-methyluridine at position 1369 (Um1369) in the 16S mitochondrial large subunit ribosomal RNA (mtLSU rRNA)
GO:0008650 rRNA (uridine-2'-O-ribose)-methyltransferase activity	IMP PMID:35177605 A late-stage assembly checkpoint of the human mitochondrial ...	ACCEPT	Summary: Knock-out and K59A/D154A catalytic-mutant complementation; the mutants leave U3039 (Um1369) unmethylated. Reason: The cleanest genetic evidence that the MRM2 catalytic site is responsible for Um1369. Core activity. Supporting Evidence: PMID:35177605 Validation of the catalytic inactivity of the human variants was obtained by RNA LC-MS2, which identified 16S mt-rRNA oligonucleotides containing U3039 solely in its non-methylated state both in MRM2 knock-out cells complemented with MRM2 K59A and MRM2 D154A , as well as in the knock-out background
GO:0008650 rRNA (uridine-2'-O-ribose)-methyltransferase activity	NAS PMID:11827451 Identification and characterization of FTSJ2, a novel human ...	ACCEPT	Summary: Homology-based proposal in the original cloning paper that FTSJ2 is a uridine-2'-O-methyltransferase like E. coli FtsJ/RrmJ. Reason: The homology-based statement is correct and was later confirmed experimentally (PMID:25074936, PMID:35177605). Supporting Evidence: PMID:11827451 FTSJ2 shares significant sequence homology with FtsJ/RrmJ, a recently identified Escherichia coli 23S rRNA uridine-2'-O-methyltransferase.
GO:0031167 rRNA methylation	IBA GO_REF:0000033	MODIFY	Summary: PAINT inference of rRNA methylation from PTN000100455. Reason: Correct node placement, but the specific process, rRNA 2'-O-methylation (GO:0000451, is_a GO:0031167), is experimentally established and already carried by the gene. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000100455 SUPPORTS TRANSFER FtsJ/RlmE clade node that also carries GO:0008650 uridine-2'-O-ribose methyltransferase activity, so the refinement to rRNA 2'-O-methylation is consistent with the node. Proposed replacements: rRNA 2'-O-methylation Supporting Evidence: PMID:25074936 are responsible for modification of human large subunit rRNA at residues
GO:0031167 rRNA methylation	NAS PMID:11827451 Identification and characterization of FTSJ2, a novel human ...	MODIFY	Summary: Homology-based statement in the FTSJ2 cloning paper. Reason: Correct but general; refined to rRNA 2'-O-methylation (GO:0000451). Proposed replacements: rRNA 2'-O-methylation Supporting Evidence: PMID:11827451 Our results suggest that FTSJ2 is likely a nucleolar RNA methyltransferase involved in eukaryotic RNA processing and modification.
GO:0140978 mitochondrial large ribosomal subunit binding	IDA PMID:34135320 Stepwise maturation of the peptidyl transferase region of hu...	ACCEPT	Summary: Cryo-EM of human mtLSU assembly intermediates with MRM2 bound near the A-loop. Reason: MRM2 is resolved on late mtLSU assembly intermediates in independent cryo-EM studies (PMID:34135320, PMID:34135318) and cosediments with the mitoribosome (PMID:25009282). Binding of the assembling mtLSU is the molecular basis of its catalysis-independent assembly-factor role (PMID:35177605), so this is treated as core rather than a mere substrate interaction. Supporting Evidence: PMID:34135318 Both the GTPBP5KO and GTPBP5IP mt-LSU assembly intermediates reveal several trapped assembly factors: the MTERF4-NSUN4 complex, MRM2, MTG1, and the MALSU1:L0R8F8:mt-ACP module PMID:34135320 Here we present eight distinct assembly intermediates of the human large mitoribosomal subunit involving seven assembly factors.
GO:1902775 mitochondrial large ribosomal subunit assembly	IDA PMID:34135318 Structural basis for late maturation steps of the human mito...	ACCEPT	Summary: Cryo-EM of GTPBP5-deficient mtLSU intermediates with MRM2 bound; MTERF4 folding of 16S rRNA enables MRM2 binding. Reason: MRM2 is a structural participant in a defined late step of mtLSU assembly. Together with the knock-out and catalytic-dead rescue data (PMID:35177605) this is a core process. Supporting Evidence: PMID:34135318 MTERF4 binding of pre-H68-71 partly orders the disordered rRNA in the mt-LSU assemblies’ subunit interface side and thereby enables MRM2 to bind
GO:1902775 mitochondrial large ribosomal subunit assembly	IDA PMID:38042949 Structural insights into the role of GTPBP10 in the RNA matu...	ACCEPT	Summary: GTPBP10/GTPBP7 cryo-EM study that orders mtLSU maturation events, including MRM2 binding to the A-loop and its GTPBP5-triggered release. Reason: The paper's structures centre on GTPBP10, and the MRM2 statements in the cached text are largely interpretive, placing MRM2 in the assembly sequence. The function is clearly correct for MRM2 (PMID:35177605, PMID:34135318), so the curator's IDA is accepted. Supporting Evidence: PMID:38042949 Finally, GTPBP5 binds to the maturation intermediate and triggers release of the A loop from the binding pocket in MRM2
GO:1902775 mitochondrial large ribosomal subunit assembly	IMP PMID:35177605 A late-stage assembly checkpoint of the human mitochondrial ...	ACCEPT	Summary: MRM2 knock-out traps mtLSU in immature states; catalytically dead K59A/D154A MRM2 rescues translation, showing that the assembly role does not require methyltransferase activity. Reason: Defining evidence for the catalysis-independent assembly-factor function. MRM2 does part of the work of assembly (it binds the intermediate and is needed for domains IV/V to fold), so this is participation, not only necessity. Supporting Evidence: PMID:35177605 As observed by the restoration of the expression of MT-CO2, both K59A and D154A MRM2 variants were able to rescue the defect in mitochondrial translation caused by knock-out of the endogenous gene despite their null methyltransferase activity. PMID:35177605 However, mitoribosome biogenesis does not depend on the methyltransferase activity of MRM2.

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