WDR6 (WD repeat-containing protein 6) is the human ortholog of yeast Trm734, functioning as the regulatory subunit of the FTSJ1-WDR6 tRNA 2'-O-methyltransferase complex. WDR6 binds directly to tRNA substrates and positions them for methylation by the catalytic subunit FTSJ1 at the wobble position 34 of specific tRNAs. The FTSJ1-WDR6 complex specifically catalyzes 2'-O-methylation at wobble position 34 on specific tRNAs, including Gm34 on tRNAPhe(GAA) and position-34 2'-O-methylation on tRNALeu(CAA). m1G37 is a prerequisite for Gm34 formation on tRNAPhe(GAA). WDR6 contains multiple WD40 repeats that form a beta-propeller scaffold critical for tRNA substrate recognition. Loss of WDR6 function impairs translation efficiency of UUU codons, particularly affecting neuronal genes with high TTT codon usage.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for cytoplasmic localization is consistent with the cytosolic function of WDR6 in tRNA modification. The FTSJ1-WDR6 complex modifies cytosolic tRNAs, and the yeast ortholog Trm734 also functions in the cytoplasm [Li et al., 2020 EMBO Rep]. Reason: Cytoplasmic localization is well-supported by phylogenetic inference from yeast Trm734 and is consistent with the cytosolic tRNA modification function. UniProt confirms cytoplasmic localization with experimental evidence from PMID:17216128. Supporting Evidence: PMID:32558197 FTSJ1 interacts with WDR6, and this interaction does not require intracellular RNAs PMID:17216128 Immunofluorescence staining revealed that WDR6 was localized in cytoplasm file:human/WDR6/WDR6-deep-research-falcon.md model: Edison Scientific Literature |
| GO:0030488 tRNA methylation | IBA GO_REF:0000033 | ACCEPT | Summary: IBA annotation for tRNA methylation is well-supported by direct experimental evidence showing WDR6 functions with FTSJ1 to catalyze 2'-O-methylation at position 34 of specific tRNAs [Li et al., 2020 EMBO Rep]. Reason: This represents a core function of WDR6. The FTSJ1-WDR6 complex catalyzes Nm34 formation on specific substrates, with Gm34 specifically demonstrated on tRNAPhe(GAA). The IBA annotation correctly captures this conserved function across eukaryotes. Supporting Evidence: PMID:32558197 FTSJ1-WDR6 could catalyze tRNA:Nm34 modification in vitro, and m1G37 is one of the prerequisites for Gm34 formation |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: IEA annotation based on UniProtKB subcellular location mapping. Consistent with IBA and IDA evidence for cytoplasmic localization. Reason: Redundant with IBA and IDA annotations but correctly identifies cytoplasmic localization. Electronic annotation is appropriately supported by curated UniProt subcellular location. Supporting Evidence: PMID:17216128 Immunofluorescence staining revealed that WDR6 was localized in cytoplasm |
| GO:0008033 tRNA processing | IEA GO_REF:0000043 | ACCEPT | Summary: IEA annotation based on UniProtKB keyword mapping. The term is appropriate but less specific than the more precise "tRNA methylation" or "wobble position ribose methylation" terms also assigned. Reason: While broader than optimal, this term correctly captures WDR6's role in tRNA processing through its function in tRNA modification. The more specific GO:0030488 (tRNA methylation) and GO:0002130 (wobble position ribose methylation) are also present and more informative. Supporting Evidence: PMID:32558197 FTSJ1-WDR6 catalyzes Gm34 on tRNAPhe(GAA) with m1G37 as a prerequisite |
| GO:0005515 protein binding | IPI PMID:17216128 Association of LKB1 with a WD-repeat protein WDR6 is implica... | REMOVE | Summary: This annotation captures WDR6 interaction with STK11/LKB1 but the term "protein binding" is uninformative. The interaction with LKB1 may modulate cell growth suppression activity. Reason: "Protein binding" (GO:0005515) is a low-information annotation that does not describe the actual molecular function. While WDR6 does interact with STK11/LKB1 (demonstrated by co-IP and yeast two-hybrid), this generic term does not capture the regulatory nature of the interaction. The core molecular function of WDR6 is tRNA binding and enzyme-substrate adaptor activity for the FTSJ1 methyltransferase. Supporting Evidence: PMID:17216128 Epub 2007 Jan 10. Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction. PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | REMOVE | Summary: High-throughput interactome study identifying WDR6 interaction with PTPN3. The term "protein binding" is uninformative for molecular function annotation. Reason: This is a high-throughput proteome-scale interactome study that does not provide functional context for the interaction. "Protein binding" as a term does not inform about WDR6's actual molecular function. Core functions are captured by enzyme regulator activity and tRNA binding terms. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Reference interactome map (HuRI) documenting binary protein-protein interactions including WDR6-PTPN3 and WDR6-GRIP1. These are high-throughput Y2H interactions. Reason: "Protein binding" is uninformative and should be replaced with more specific molecular function terms. These interactions from the HuRI reference map lack functional characterization. The core function of WDR6 as a tRNA methyltransferase regulator is better captured by existing enzyme regulator and tRNA binding annotations. Supporting Evidence: PMID:32296183 Apr 8. A reference map of the human binary protein interactome. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: IDA annotation based on immunofluorescence data from the Human Protein Atlas. Cytosolic localization is consistent with WDR6's role in modifying cytosolic tRNAs. Reason: Cytosolic localization is appropriate for WDR6's function in cytosolic tRNA modification. This is consistent with experimental data from PMID:17216128 showing cytoplasmic localization. Supporting Evidence: PMID:17216128 Immunofluorescence staining revealed that WDR6 was localized in cytoplasm |
| GO:0140767 enzyme-substrate adaptor activity | IDA PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible... | ACCEPT | Summary: WDR6 functions as an enzyme-substrate adaptor, positioning tRNA substrates for methylation by FTSJ1. Gel mobility shift assays showed FTSJ1-WDR6 complex has enhanced tRNA binding compared to FTSJ1 alone, with WDR6 contributing the substrate binding capacity [Li et al., 2020]. Reason: This is a core molecular function of WDR6. The paper demonstrates that "FTSJ1 is the SAM-binding catalytic subunit and has weaker tRNA-binding affinity, while WDR6 mainly plays a role in binding to tRNA substrates." This precisely describes enzyme-substrate adaptor activity where WDR6 recruits and positions tRNA for catalysis by FTSJ1. Supporting Evidence: PMID:32558197 FTSJ1 is the SAM-binding catalytic subunit and has weaker tRNA-binding affinity, while WDR6 mainly plays a role in binding to tRNA substrates PMID:32558197 The binding affinity of FTSJ1 alone or FTSJ1-WDR6 for tRNA analyzed by the gel mobility shift assay |
| GO:0030234 enzyme regulator activity | IDA PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible... | MODIFY | Summary: WDR6 regulates FTSJ1 tRNA methyltransferase activity by providing substrate binding and positioning. The FTSJ1-WDR6 complex reconstitutes 2'-O-methylation activity at position 34, which cannot be achieved by FTSJ1 alone. Reason: While "enzyme regulator activity" is not incorrect, a more specific term exists. WDR6 functions specifically as an activator of tRNA methyltransferase activity by enabling substrate binding and positioning for FTSJ1. Proposed replacements: tRNA methyltransferase activator activity Supporting Evidence: PMID:32558197 we reconstitute the 2'-O-methylation activity of the FTSJ1-WDR6 complex in vitro, which occurs at position 34 of specific tRNAs |
| GO:0000049 tRNA binding | IDA PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible... | ACCEPT | Summary: WDR6 directly binds tRNA substrates as demonstrated by gel mobility shift assays. The FTSJ1-WDR6 complex shows enhanced tRNA binding compared to FTSJ1 alone, with WDR6 providing the primary tRNA binding capacity [Li et al., 2020]. Reason: This is a core molecular function of WDR6. The gel mobility shift assays clearly demonstrate that WDR6 enhances tRNA binding when complexed with FTSJ1, and the paper states WDR6 "mainly plays a role in binding to tRNA substrates." Supporting Evidence: PMID:32558197 WDR6 mainly plays a role in binding to tRNA substrates PMID:32558197 The binding affinity of FTSJ1 alone or FTSJ1-WDR6 for tRNA analyzed by the gel mobility shift assay |
| GO:0002130 wobble position ribose methylation | IDA PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible... | ACCEPT | Summary: The FTSJ1-WDR6 complex specifically catalyzes 2'-O-methylation at the wobble position (position 34) of tRNAs. This is directly demonstrated as Gm34 formation on tRNAPhe(GAA), with broader Nm34 activity on specific position-34 tRNA substrates including tRNALeu(CAA) [Li et al., 2020]. Reason: This is a core biological process for WDR6. The paper provides direct evidence that "FTSJ1-WDR6 could catalyze tRNA:Nm34 modification in vitro" at the wobble position (position 34). This precisely describes the 2'-O-ribose methylation at position 34. Supporting Evidence: PMID:32558197 FTSJ1-WDR6 catalyzes Gm34 on tRNAPhe(GAA) with m1G37 as a prerequisite PMID:32558197 two tRNAs, tRNAPhe(GAA) and tRNALeu(CAA), are the substrates of FTSJ1‐WDR6 for catalyzing 2′‐O‐methylation at position 34 |
| GO:0070314 G1 to G0 transition | IPI PMID:17216128 Association of LKB1 with a WD-repeat protein WDR6 is implica... | KEEP AS NON CORE | Summary: WDR6 coexpression with LKB1 enhanced G1 arrest in HeLa cells and induced p27(Kip1) expression. However, this appears to be a secondary effect through interaction with LKB1 rather than a core function of WDR6. Reason: While WDR6 can synergize with LKB1 for cell cycle regulation, this is likely a secondary/pleiotropic effect rather than the core molecular function. The primary function of WDR6 is tRNA methylation regulation with FTSJ1. The cell cycle effects observed through LKB1 interaction may be indirect consequences of altered translation or represent a moonlighting function. Supporting Evidence: PMID:17216128 WDR6 was able to synergize with LKB1 in cell cycle G1 arrest in Hela cells |
| GO:0003723 RNA binding | HDA PMID:22658674 Insights into RNA biology from an atlas of mammalian mRNA-bi... | ACCEPT | Summary: High-throughput interactome capture study identifying WDR6 as an mRNA-binding protein. The term is broad but consistent with WDR6's demonstrated tRNA binding activity. Reason: While derived from a high-throughput study, RNA binding is consistent with WDR6's well-characterized tRNA binding function. The more specific term GO:0000049 (tRNA binding) is also present and more informative for WDR6's primary function. Supporting Evidence: PMID:32558197 WDR6 mainly plays a role in binding to tRNA substrates PMID:22658674 May 31. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. |
| GO:0010507 negative regulation of autophagy | IMP PMID:22354037 Genome-wide siRNA screen reveals amino acid starvation-induc... | KEEP AS NON CORE | Summary: The GOA annotation traces WDR6 to a genome-wide siRNA screen for starvation-induced autophagy regulators. The cached abstract reports nine novel regulators from the screen but names only SCOC and WAC, so WDR6 is treated here as an uncharacterized screen hit rather than a mechanistically defined autophagy factor. This may be a secondary effect of altered translation when tRNA modification is impaired. Reason: The source paper supports a screen-level association with starvation-induced autophagy but does not name WDR6 in the cached abstract, and no direct mechanism is available here. This is therefore kept as a non-core phenotype, plausibly a downstream consequence of altered translation efficiency when tRNA wobble position modification is disrupted. The core function of WDR6 is tRNA modification. Supporting Evidence: PMID:22354037 Using stringent validation criteria, our screen identified nine novel autophagy regulators. |
| GO:0008180 COP9 signalosome | IDA PMID:18850735 Characterization of the human COP9 signalosome complex using... | UNDECIDED | Summary: WDR6 was identified as colocalizing with the COP9 signalosome in a proteomic study using affinity purification and mass spectrometry. This was a high-throughput study without specific characterization of WDR6 function in this context. Reason: The colocalization with COP9 signalosome was identified in a proteomics study but lacks functional characterization for WDR6 specifically. The relationship between WDR6's tRNA modification function and COP9 signalosome is unclear. This may represent a non-core function or experimental artifact. Supporting Evidence: PMID:18850735 Characterization of the human COP9 signalosome complex using affinity purification and mass spectrometry. PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs. |
| GO:0005737 cytoplasm | IDA PMID:17216128 Association of LKB1 with a WD-repeat protein WDR6 is implica... | ACCEPT | Summary: Direct experimental evidence for cytoplasmic localization of WDR6 via immunofluorescence staining showing colocalization with STK11/LKB1 in the cytoplasm. Reason: High-quality experimental evidence for cytoplasmic localization. Consistent with WDR6's function in cytosolic tRNA modification. Supporting Evidence: PMID:17216128 Immunofluorescence staining revealed that WDR6 was localized in cytoplasm, similar to the localization of LKB1 |
| GO:0008285 negative regulation of cell population proliferation | IDA PMID:17216128 Association of LKB1 with a WD-repeat protein WDR6 is implica... | KEEP AS NON CORE | Summary: WDR6 coexpression with LKB1 inhibited colony formation and enhanced LKB1-induced cell growth suppression in HeLa cells. This appears to be mediated through LKB1 interaction rather than a direct function of WDR6. Reason: The antiproliferative effect is dependent on LKB1 coexpression and appears to be a secondary effect of WDR6-LKB1 interaction rather than a core WDR6 function. The primary molecular function of WDR6 is tRNA methyltransferase regulation. Cell proliferation effects may be indirect consequences of altered translation or represent a moonlighting function through LKB1 signaling. Supporting Evidence: PMID:17216128 coexpression of WDR6 with LKB1 enhanced the inhibitory effect of LKB1 on Hela cell proliferation |
| GO:0002129 wobble position guanine ribose methylation | IDA PMID:32558197 Intellectual disability-associated gene ftsj1 is responsible... | NEW | Summary: The FTSJ1-WDR6 complex specifically catalyzes 2'-O-methylation of guanosine at the wobble position 34, producing Gm34 on tRNAPhe(GAA). This is demonstrated directly by UPLC-MS/MS analysis [Li et al., 2020]. Reason: This more specific term captures the precise modification catalyzed by FTSJ1-WDR6 on tRNAPhe(GAA) - 2'-O-methylation of guanosine at position 34. The paper directly demonstrates "FTSJ1-WDR6 catalyzes Gm34 on tRNAPhe(GAA)." Supporting Evidence: PMID:32558197 FTSJ1-WDR6 catalyzes Gm34 on tRNAPhe(GAA) with m1G37 as a prerequisite PMID:32558197 Quantification of the Cm/A and Gm/A of tRNAPhe(GAA) |
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Download this section (compressed HTML)Q: What structural features of WDR6 determine tRNA substrate specificity? Yeast Trm734 structural studies have identified residues critical for Nm34 formation, but corresponding residues in human WDR6 have not been mapped.
Q: Does WDR6 have functions independent of FTSJ1? WDR6 interacts with LKB1 and affects cell cycle and autophagy, but it is unclear if these are mediated through altered tRNA modification or represent separate FTSJ1-independent functions.
Experiment: Structure determination of FTSJ1-WDR6-tRNA complex by cryo-EM. Recent cryo-EM structure of FTSJ1-THADA provides a template. FTSJ1-WDR6 structure would reveal how WDR6 WD40 domains position tRNA for Nm34 modification and identify key residues for substrate recognition.
Hypothesis: WDR6 WD40 domains form a scaffold that positions the tRNA anticodon loop at the FTSJ1 active site
Experiment: Generate separation-of-function WDR6 mutants based on yeast Trm734 mutational analysis. Create WDR6 variants that retain FTSJ1 binding but lose tRNA modification activity to separate modification-dependent from modification-independent phenotypes in cellular assays.
Hypothesis: Some WDR6 phenotypes (autophagy, cell cycle effects) may be independent of tRNA modification
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The structural basis by which human WDR6 selects and positions position-34 tRNA substrates for FTSJ1 remains incompletely resolved.
NARROWING BIOLOGYCURATION MF_DARK
What is known: The review already accepts WDR6 as the FTSJ1 regulatory/adaptor subunit for wobble-position ribose methylation. The unresolved gap is the human structure-function mechanism: which WDR6 surfaces, FTSJ1 interfaces, and tRNA features determine Nm34 substrate selectivity.
Significance: Resolving this gap would strengthen the molecular-function representation of WDR6 beyond generic adaptor and tRNA-binding terms, and would clarify how human substrate specificity differs from yeast Trm7-Trm734.
What would resolve it: High-resolution human FTSJ1-WDR6-tRNA structures, paired with separation-of-function WDR6 mutants and tRNA substrate panels, should define the substrate-recognition determinants that support precise curation.
Provenance (the field's own admissions):
Gap: The relationship between WDR6's core tRNA-modification role and its reported LKB1, insulin signaling, lipogenesis, viral restriction, autophagy, and ubiquitin-ligase-associated phenotypes remains unresolved.
OPEN BIOLOGYCURATION BP_DARK
What is known: The core function is WDR6-dependent FTSJ1 Nm34 tRNA modification. Existing cell-cycle and autophagy annotations are kept as non-core or undecided because current evidence does not distinguish direct WDR6 moonlighting functions from downstream consequences of altered translation or context-specific scaffolding.
Significance: Resolving this gap would prevent broad process over-annotation while identifying any bona fide WDR6-specific signaling or proteostasis functions that should be curated separately from the FTSJ1-WDR6 tRNA pathway.
What would resolve it: Separation-of-function alleles that retain FTSJ1 binding or tRNA modification while disrupting candidate signaling or ubiquitin-ligase interfaces should be tested across the reported cellular contexts.
Provenance (the field's own admissions):
Gap: WDR6's tissue-specific and disease-relevant functions remain poorly defined, especially for brain, liver, cancer, and variant-associated phenotypes.
OPEN BIOLOGYCURATION BP_DARK
What is known: WDR6 is mechanistically linked to FTSJ1-dependent tRNA modification and has disease-context evidence from FTSJ1 intellectual-disability biology, metabolic studies, HCC studies, and GWAS signals. The gap is whether WDR6 variants or tissue-specific regulation cause distinct human phenotypes and which of those phenotypes are annotation-worthy biology.
Significance: Resolving this gap would clarify whether WDR6 should receive disease- or tissue-context biological-process annotations, or whether those observations should remain contextual evidence around a conserved tRNA-modification module.
What would resolve it: Patient-variant functional assays, tissue-specific WDR6 perturbation, and rescue with tRNA-modification-competent versus separation-of-function WDR6 alleles should connect genotype, tissue context, and molecular mechanism.
Provenance (the field's own admissions):
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