WDR6 (Q9NNW5): A Comprehensive Research Report on tRNA Methyltransferase Regulator Function

Introduction

WDR6 (WD repeat-containing protein 6) is a human protein encoded by the WDR6 gene located on chromosome 15q21. The protein consists of 1,121 amino acids and contains 11 WD-repeat domains organized in a characteristic β-propeller structure [li-2000-wdr6-cloning-abstract]. According to UniProt, WDR6's primary function is as a tRNA (34-2'-O)-methyltransferase regulator, and this role has been substantiated by biochemical reconstitution studies demonstrating that WDR6 forms an obligate complex with FTSJ1 to catalyze 2'-O-methylation at position 34 of specific transfer RNAs [li-2020-ftsj1-wdr6-abstract].

The discovery of WDR6's role in tRNA modification represents a significant advance in understanding epitranscriptomic regulation of translation. Based on articles retrieved from PubMed, Li et al. (2020) demonstrated for the first time that the FTSJ1-WDR6 complex reconstituted in vitro is capable of 2'-O-methylation activity at position 34 of specific tRNAs, with the modification requiring pre-existing 1-methylguanosine at position 37 (mG37) as a prerequisite (DOI). This finding established WDR6 as the human functional equivalent of yeast Trm734, a component of the conserved tRNA modification machinery.

Molecular Function: tRNA 2'-O-Methylation

The primary and best-characterized molecular function of WDR6 is as a regulatory subunit of the FTSJ1 tRNA 2'-O-methyltransferase complex. WDR6 does not possess catalytic activity itself; rather, it serves as a scaffold protein that binds transfer RNA and positions it correctly for methylation by FTSJ1 [li-2020-ftsj1-wdr6-summary].

The FTSJ1-WDR6 complex specifically catalyzes 2'-O-methylation at the wobble position 34 (Nm34) of certain tRNAs, producing Gm34 (2'-O-methylguanosine) in tRNA-Phe(GAA), tRNA-Trp(CCA), and tRNA-Leu(UAA). FTSJ1 alone cannot perform this catalysis; the presence of WDR6 is essential for enzymatic activity. In vitro reconstitution experiments demonstrated that neither FTSJ1 nor WDR6 alone could methylate tRNA substrates, but the binary FTSJ1-WDR6 complex exhibited robust Gm34 formation activity [li-2020-ftsj1-wdr6-abstract].

The catalytic mechanism involves S-adenosyl-L-methionine (SAM) as the methyl donor. Isothermal titration calorimetry confirmed that FTSJ1 binds SAM directly, while WDR6 primarily functions in substrate recognition and positioning. A critical finding is that the modification requires pre-existing mG37 (1-methylguanosine at position 37) as a prerequisite, establishing a hierarchical order of tRNA modifications where G37 must first be methylated before position 34 can be modified [li-2020-ftsj1-wdr6-summary].

It is important to note that FTSJ1 forms a separate complex with THADA (another regulatory protein) to catalyze 2'-O-methylation at position 32 (Nm32) of tRNAs. According to PubMed, Ishiguro et al. (2025) solved the cryo-EM structure of the human FTSJ1-THADA complex and demonstrated that the interaction mode between FTSJ1 and THADA is distinct from that between FTSJ1 and WDR6 (DOI). This division of labor—WDR6 for position 34 and THADA for position 32—ensures precise and position-specific tRNA modification.

Structural Features and Protein Architecture

WDR6 was first cloned and characterized by Li et al. (2000), who identified it as a novel WD-repeat protein containing 11 WD-repeat units arranged in two distinct groups separated by a putative transmembrane domain [li-2000-wdr6-cloning-abstract]. This architecture is unique among human WD-repeat proteins and is conserved across eukaryotes, with homologs found in Arabidopsis thaliana and yeast (Saccharomyces cerevisiae Trm734/YPL183c).

Structural insights into the FTSJ1-WDR6 complex come primarily from crystallographic studies of the yeast ortholog Trm7-Trm734. According to PubMed, Hirata et al. (2019) solved the crystal structure of the Trm7-Trm734 complex and revealed that Trm734 (the WDR6 ortholog) consists of three WD40 β-propeller domains designated BPA, BPB, and BPC (DOI). BPA and BPC form a unique V-shaped cleft that docks to the methyltransferase Trm7, while BPB contains a positively charged surface that interacts with the D-arm of the tRNA substrate [hirata-2019-trm7-trm734-structure-summary].

The C-terminal region of FTSJ1 (around residue 221) is essential for binding to WDR6. Li et al. identified the peptide sequence FNQLDGPTRIIVPFVTCGDLSS in FTSJ1 as the critical motif for WDR6 interaction using domain mapping and proximity labeling experiments [li-2020-ftsj1-wdr6-summary]. This binding interface is distinct from the FTSJ1-THADA interaction, allowing FTSJ1 to form mutually exclusive complexes with either WDR6 or THADA depending on the target modification site.

Subcellular Localization

WDR6 and the FTSJ1-WDR6 complex are predominantly cytoplasmic. Immunofluorescence microscopy of Flag-tagged FTSJ1 in HEK293T cells demonstrated that the protein is mainly located in the cytoplasm, with only a small fraction detected in the nucleus [li-2020-ftsj1-wdr6-summary]. This localization is consistent with WDR6's function in modifying cytoplasmic tRNAs that are involved in translation.

Subcellular fractionation experiments confirmed this distribution, with Western blotting showing FTSJ1 predominantly in cytosolic fractions using α-tubulin as a cytoplasmic marker and lamin A/C as a nuclear marker. The cytoplasmic localization was also confirmed in studies of WDR6's interaction with LKB1, where immunofluorescence staining revealed that WDR6 is localized in the cytoplasm, similar to LKB1 (DOI) [xie-2007-wdr6-lkb1-abstract].

Biological Processes and Pathways

Translation Regulation and Codon-Specific Effects

The 2'-O-methylation at position 34 of tRNAs catalyzed by FTSJ1-WDR6 has significant consequences for translation fidelity and efficiency. Loss of Gm34 modification in tRNA-Phe(GAA) specifically reduces translation efficiency of the UUU codon (but not the synonymous UUC codon), demonstrating codon-specific effects of this epitranscriptomic modification [li-2020-ftsj1-wdr6-summary].

Bioinformatic analysis revealed that approximately 40% of genes with high TTT codon bias are related to brain and nervous system functions. This finding provides a mechanistic link between WDR6/FTSJ1 function and the neurological phenotypes observed in patients with FTSJ1 mutations, who present with non-syndromic X-linked intellectual disability (NSXLID) [li-2020-ftsj1-wdr6-abstract].

Hierarchical tRNA Modification

The modifications at positions 32, 34, and 37 of the anticodon loop are interdependent and occur in a specific hierarchical order. In tRNA-Phe(GAA), the hypermodification wybutosine (yW) or peroxywybutosine (o2yW) at position 37 depends on prior Cm32 and Gm34 formation. FTSJ1 knockout cells show decreased o2yW37 levels and accumulated mG37, indicating that the loss of ribose methylation at positions 32 and 34 impedes the conversion of mG37 to hypermodified forms. This hierarchical relationship is conserved between yeast and humans [li-2020-ftsj1-wdr6-summary].

Cell Cycle Regulation via LKB1

Beyond its role in tRNA modification, WDR6 has been implicated in cell cycle regulation through interaction with the tumor suppressor kinase LKB1 (also known as STK11). Xie et al. (2007) identified WDR6 as an LKB1-interacting protein using yeast two-hybrid screening and demonstrated that coexpression of WDR6 with LKB1 enhances the inhibitory effect of LKB1 on cell proliferation (DOI) [xie-2007-wdr6-lkb1-abstract].

Mechanistically, WDR6 synergizes with LKB1 to induce G1 cell cycle arrest by upregulating the cyclin-dependent kinase inhibitor p27(Kip1). Coexpression of WDR6 and LKB1 significantly elevated p27 promoter activity compared to LKB1 alone. These findings suggest that WDR6 participates in the tumor suppressor pathway of LKB1, mutations in which cause Peutz-Jeghers syndrome with increased cancer predisposition.

Insulin Signaling and Longevity

WDR6 has been linked to insulin/IGF-1 signaling pathways in the brain. According to PubMed, Chiba et al. (2007) identified WDR6 as interacting with insulin receptor substrate 4 (IRS-4) in rat brain and found that WDR6 is abundantly expressed in the hypothalamus (DOI) [chiba-2007-wdr6-irs4-abstract].

Notably, WDR6 expression in the hypothalamic arcuate nucleus was decreased under conditions associated with extended lifespan, including caloric restriction and growth hormone-antisense transgenic rats. Conversely, insulin and IGF-1 treatment increased WDR6 expression in hypothalamus-derived GT1-7 cells. These findings suggest WDR6 may participate in the regulation of feeding behavior and longevity through insulin/IGF-1 signaling in the brain.

Hepatic De Novo Lipogenesis

A recent study identified an unexpected role for WDR6 in hepatic lipid metabolism. According to PubMed, Zhang et al. (2023) demonstrated that WDR6 promotes hepatic de novo lipogenesis (DNL) during insulin resistance by interacting with PPP1CB (protein phosphatase 1 catalytic subunit beta) (DOI) [zhang-2023-wdr6-lipogenesis-abstract].

Mechanistically, WDR6 facilitates PPP1CB-mediated dephosphorylation of the carbohydrate-responsive element-binding protein (ChREBP), leading to ChREBP activation and nuclear translocation. Activated ChREBP then induces expression of lipogenic genes. Importantly, WDR6 knockdown in insulin-resistant mice reduced hepatic steatosis and improved glucose homeostasis, suggesting WDR6 as a potential therapeutic target for metabolic disorders including non-alcoholic fatty liver disease (NAFLD).

Innate Immunity and Viral Defense

WDR6 has been identified as a host restriction factor for vaccinia virus. According to PubMed, Sivan et al. (2015) performed a genome-wide siRNA screen and discovered that knockdown of WDR6 (along with SAMD9) dramatically enhanced replication of a vaccinia virus mutant lacking the C7L and K1L genes (DOI) [sivan-2015-wdr6-vaccinia-abstract].

CRISPR/Cas9 knockout of WDR6 in HeLa cells rendered them permissive for replication of the K1L(-)C7L(-) mutant virus. WDR6 appears to act independently of SAMD9 in this pathway, as no direct interactions between WDR6 and SAMD9 or the viral K1/C7 proteins were detected.

A follow-up study by Sivan et al. (2018) demonstrated that the restriction hierarchy is SAMD9 > WDR6 > FTSJ1, with the C7/K1 deletion mutant reaching wild-type replication levels only in SAMD9 knockout cells (DOI) [sivan-2018-wdr6-ftsj1-vaccinia-abstract]. Importantly, the co-identification of WDR6 but not THADA from the genome-wide screen strongly suggests that tRNA methylation at position 34 (catalyzed by FTSJ1-WDR6) is specifically important for host restriction, while position 32 modification (catalyzed by FTSJ1-THADA) is not. This finding directly links WDR6's tRNA modification function to innate antiviral immunity and suggests that proper wobble position modification is required for efficient translation during viral infection.

E3 Ubiquitin Ligase Complex Association

WDR6 has been identified as a component of a Cullin 4-DDB1 E3 ubiquitin ligase complex. According to PubMed, Xue et al. (2019) used affinity pull-down and mass spectrometry to identify the Cul4-DDB1-WDR3/WDR6 complex as a binding partner of SPAK and OSR1 kinases, which regulate ion homeostasis under osmotic stress (DOI) [xue-2019-wdr6-spak-abstract].

The interaction between WDR6 and SPAK/OSR1 requires phosphorylation of the S-motif by WNK kinases, suggesting a phosphorylation-dependent regulatory mechanism linking osmotic stress signaling to potential protein degradation pathways. This function of WDR6 as a substrate receptor for the Cul4-DDB1 E3 ligase represents a distinct molecular role from its tRNA modification function.

Cancer and Tumor Immune Microenvironment

A significant role for WDR6 in hepatocellular carcinoma (HCC) was identified through its E3 ubiquitin ligase function. Zhang et al. (2023) demonstrated that WDR6 promotes HCC progression by targeting the tumor suppressor UVRAG for ubiquitin-mediated degradation via the CUL4A-DDB1-ROC1 E3 ligase complex (DOI) [zhang-2023-wdr6-hcc-abstract]. WDR6 uses a distinctive WDxR motif to bind UVRAG and direct it to this degradation pathway.

Mechanistically, UVRAG degradation prevents autophagic degradation of NF-κB p65, leading to increased chromatin accessibility at the TNFα locus. This results in elevated TNFα production, which has profound effects on the tumor immune microenvironment: it increases intratumoral myeloid-derived suppressor cells (MDSCs) while reducing CD8+ T cell infiltration, thereby creating an immunosuppressive environment that favors tumor growth. Importantly, TNFα also activates NF-κB signaling to upregulate WDR6 transcription, establishing a self-reinforcing positive feedback loop.

While WDR6 knockdown does not substantially alter HCC cell proliferation or invasion in vitro, it dramatically suppresses tumor growth and lung metastasis in immune-competent mice. This finding underscores the importance of WDR6's role in shaping the tumor immune microenvironment rather than direct effects on cancer cell behavior. Clinically, the WDR6/UVRAG/NF-κB pathway is hyperactivated in HCC patients and predicts poor prognosis. A therapeutic approach using WDxR-mimetic peptides to disrupt the WDR6-UVRAG interaction enhanced the efficacy of anti-PD-L1 immunotherapy in preclinical models.

Evidence Summary

The evidence for WDR6's function as a tRNA methyltransferase regulator is robust and includes:

1. Biochemical reconstitution: In vitro assays demonstrating that purified FTSJ1-WDR6 complex (but not either protein alone) catalyzes Gm34 formation on specific tRNAs [li-2020-ftsj1-wdr6-abstract].

2. Genetic studies: CRISPR knockout of WDR6 in HEK293T cells specifically abolishes Gm34 modification of tRNA-Phe while leaving Cm32 intact, confirming position-specific function [li-2020-ftsj1-wdr6-summary].

3. Structural studies: Crystal structure of yeast Trm7-Trm734 complex reveals molecular basis for tRNA recognition and positioning by the WDR6 ortholog [hirata-2019-trm7-trm734-structure-abstract].

4. Mass spectrometry: UPLC-MS/MS analysis confirming loss of specific nucleoside modifications in knockout cells [li-2020-ftsj1-wdr6-summary].

5. Evolutionary conservation: The Trm7-Trm734 system is conserved from yeast to humans, and human FTSJ1/WDR6 can complement yeast deletion mutants [li-2020-ftsj1-wdr6-abstract].

Evidence for alternative functions (LKB1 interaction, insulin signaling, lipogenesis, viral restriction) comes from independent yeast two-hybrid screens, co-immunoprecipitation, and genetic manipulation studies, though these functions may be secondary to or independent from the tRNA modification role.

Disease Associations

While no human diseases have been directly attributed to WDR6 mutations, the protein has been implicated in several pathological contexts:

1. Intellectual disability: Through its role in the FTSJ1 complex, WDR6 function is relevant to NSXLID caused by FTSJ1 mutations, as both proteins are required for proper tRNA modification [li-2020-ftsj1-wdr6-abstract].

2. Obsessive-compulsive disorder: According to PubMed, a large genome-wide association study (GWAS) of 53,660 OCD cases identified WDR6 as one of 25 genes classified as most likely causal candidates for OCD (DOI).

3. Metabolic disorders: WDR6's role in promoting hepatic lipogenesis during insulin resistance suggests involvement in NAFLD and metabolic syndrome [zhang-2023-wdr6-lipogenesis-abstract].

4. Hepatocellular carcinoma: WDR6 promotes HCC progression through its E3 ubiquitin ligase function by targeting UVRAG for degradation, which remodels the tumor immune microenvironment. WDR6 expression predicts poor prognosis in HCC patients, and targeting WDR6 enhances anti-PD-L1 immunotherapy efficacy [zhang-2023-wdr6-hcc-abstract].

5. Other cancers: WDR6 interaction with tumor suppressor LKB1 and its role in the Cul4-DDB1 E3 ligase complex suggest potential broader involvement in tumorigenesis beyond HCC.

Open Questions

Despite significant advances in understanding WDR6 function, several important questions remain:

1. Structural basis for human FTSJ1-WDR6 complex: While the yeast structure has been solved, high-resolution structures of the human FTSJ1-WDR6 complex with tRNA substrate would provide crucial insights into the mechanism of position 34-specific methylation and potential therapeutic targeting.

2. Coordination of multiple functions: How WDR6's tRNA modification function relates to its roles in LKB1 signaling, insulin signaling, lipogenesis, and viral restriction remains unclear. Are these independent functions, or does tRNA modification status influence these pathways?

3. Tissue-specific regulation: WDR6 is ubiquitously expressed, but its specific functions may vary by tissue. The mechanisms controlling tissue-specific WDR6 activity, particularly in brain versus liver, need further investigation.

4. Clinical relevance of WDR6 variants: While WDR6 has been identified in GWAS for OCD and other conditions, the functional consequences of specific variants and their contribution to disease pathogenesis remain to be determined.

5. Therapeutic potential: Could WDR6 be targeted pharmacologically for metabolic disorders given its role in hepatic lipogenesis? What would be the consequences on tRNA modification and translation?

6. Interplay with THADA: How cells coordinate FTSJ1-WDR6 (for Nm34) and FTSJ1-THADA (for Nm32) complex formation to achieve proper sequential tRNA modification is not fully understood.

References

1. li-2020-ftsj1-wdr6: Li J, Wang YN, Xu BS, Liu YP, Zhou M, Long T, Li H, Dong H, Nie Y, Chen PR, Wang ED, Liu RJ. Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs. EMBO Rep. 2020;21(8):e50095. PMID: 32558197. DOI: 10.15252/embr.202050095

2. hirata-2019-trm7-trm734-structure: Hirata A, Okada K, Yoshii K, Shiraishi H, Saijo S, Yonezawa K, Shimizu N, Hori H. Structure of tRNA methyltransferase complex of Trm7 and Trm734 reveals a novel binding interface for tRNA recognition. Nucleic Acids Res. 2019;47(20):10942-10955. PMID: 31586407. DOI: 10.1093/nar/gkz856

3. li-2000-wdr6-cloning: Li D, Burch P, Gonzalez O, Kashork CD, Shaffer LG, Bachinski LL, Roberts R. Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene. Biochem Biophys Res Commun. 2000;274(1):117-23. PMID: 10903905. DOI: 10.1006/bbrc.2000.3012

4. xie-2007-wdr6-lkb1: Xie X, Wang Z, Chen Y. Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction. Mol Cell Biochem. 2007;301(1-2):115-22. PMID: 17216128. DOI: 10.1007/s11010-006-9402-5

5. chiba-2007-wdr6-irs4: Chiba T, Inoue D, Mizuno A, Komatsu T, Fujita S, Kubota H, et al. Identification and characterization of an insulin receptor substrate 4-interacting protein in rat brain: implications for longevity. Neurobiol Aging. 2009;30(3):474-82. PMID: 17720279. DOI: 10.1016/j.neurobiolaging.2007.07.008

6. sivan-2015-wdr6-vaccinia: Sivan G, Ormanoglu P, Buehler EC, Martin SE, Moss B. Identification of Restriction Factors by Human Genome-Wide RNA Interference Screening of Viral Host Range Mutants Exemplified by Discovery of SAMD9 and WDR6 as Inhibitors of the Vaccinia Virus K1L-C7L- Mutant. mBio. 2015;6(4):e01122. PMID: 26242627. DOI: 10.1128/mBio.01122-15

7. zhang-2023-wdr6-lipogenesis: Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice. Nat Metab. 2023;5:1574-1590. PMID: 37735236. DOI: 10.1038/s42255-023-00896-7

8. xue-2019-wdr6-spak: The Cul4-DDB1-WDR3/WDR6 Complex Binds SPAK and OSR1 Kinases in a Phosphorylation-Dependent Manner. ChemBioChem. 2019;20(23):2935-2944. PMID: 31614064. DOI: 10.1002/cbic.201900454

9. ishiguro-2025-ftsj1-thada: Ishiguro K, Fujimura A, Shirouzu M. Structural insights into tRNA recognition of the human FTSJ1-THADA complex. Commun Biol. 2025;8(1):893. PMID: 40483304. DOI: 10.1038/s42003-025-08278-3

10. ocd-gwas-2025: Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder. Nat Genet. 2025. PMID: 40360802. DOI: 10.1038/s41588-025-02189-z

11. angelova-2020-trm7-drosophila: Angelova MT, et al. tRNA 2'-O-methylation by a duo of TRM7/FTSJ1 proteins modulates small RNA silencing in Drosophila. Nucleic Acids Res. 2020;48(4):2050-2072. PMID: 31943105. DOI: 10.1093/nar/gkaa002

12. zhang-2023-wdr6-hcc: Zhang H, Chen G, Feng X, Song H, et al. Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression. EMBO Mol Med. 2023;15(5):e15924. PMID: 36947051. DOI: 10.15252/emmm.202215924

13. sivan-2018-wdr6-ftsj1-vaccinia: Sivan G, Ormanoglu P, Buehler EC, Martin SE, Moss B. Human Host Range Restriction of the Vaccinia Virus C7/K1 Double Deletion Mutant Is Mediated by an Atypical Mode of Translation Inhibition. J Virol. 2018;92(23):e01329-18. PMID: 30209174. DOI: 10.1128/JVI.01329-18

Citations

1. chiba-2007-wdr6-irs4-abstract.md
2. hirata-2019-trm7-trm734-structure-abstract.md
3. hirata-2019-trm7-trm734-structure-summary.md
4. ishiguro-2025-ftsj1-thada-abstract.md
5. li-2000-wdr6-cloning-abstract.md
6. li-2020-ftsj1-wdr6-abstract.md
7. li-2020-ftsj1-wdr6-summary.md
8. sivan-2015-wdr6-vaccinia-abstract.md
9. sivan-2018-wdr6-ftsj1-vaccinia-abstract.md
10. xie-2007-wdr6-lkb1-abstract.md
11. xue-2019-wdr6-spak-abstract.md
12. zhang-2023-wdr6-hcc-abstract.md
13. zhang-2023-wdr6-lipogenesis-abstract.md

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Comprehensive Research Report: Human WDR6 (UniProt Q9NNW5)

Abstract
WDR6 is a human WD repeat–containing protein (WD40 β-propeller family) that functions as the regulatory partner (human ortholog of yeast Trm734) for the S-adenosyl-L-methionine (SAM)-dependent tRNA 2′-O-methyltransferase FTSJ1 (yeast Trm7). In human cells, the FTSJ1–WDR6 complex installs 2′-O-methylation at position 34 (Nm34; notably Gm34) on specific cytosolic tRNAs, whereas FTSJ1–THADA installs Nm32 at position 32; the complexes are mechanistically distinct. Loss of FTSJ1-dependent Nm modifications alters codon-specific translation and is associated with nonsyndromic X-linked intellectual disability (NSXLID), with WDR6 implicated as the position-34–directing regulatory subunit. Recent structural, biochemical, and genetic studies across 2020–2024 clarify complex composition, prerequisites for catalysis, substrate specificity, and translational consequences. (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2, graille2022divisionoflabor pages 25-28, brazane2023functionsofthe pages 49-54, funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10, ishiguro2025structuralinsightsinto pages 1-2)

1) Identity verification and key definitions
- Gene/protein identity: WDR6 (WD repeat–containing protein 6) in Homo sapiens is a WD40 β-propeller protein that acts as the regulatory/auxiliary subunit for the tRNA 2′-O-methyltransferase FTSJ1 (ortholog of yeast Trm7), specifically for Nm at position 34 in the anticodon loop. This is consistent with WD40 domain proteins serving as scaffolding/positioning subunits in RNA methyltransferase holoenzymes and with the assignment of WDR6 as the human Trm734 ortholog in epitranscriptomic literature (WIREs RNA, May 2022; DOI: 10.1002/wrna.1673; https://doi.org/10.1002/wrna.1673). (graille2022divisionoflabor pages 25-28)
- Division of catalytic versus regulatory roles: FTSJ1 is the SAM-dependent catalytic subunit; WDR6 contributes primarily to substrate recognition/positioning to enable Nm34 formation, analogous to yeast Trm7–Trm734 architecture (EMBO Reports, Jun 2020; DOI: 10.15252/embr.202050095; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2)
- Contrast with THADA: FTSJ1 also forms a distinct complex with THADA to install Nm32 at tRNA position 32; human THADA–FTSJ1 structural details have recently been elucidated, underscoring partner-specific substrate engagement modes (Communications Biology, Jun 2025; DOI: 10.1038/s42003-025-08278-3; https://doi.org/10.1038/s42003-025-08278-3). (ishiguro2025structuralinsightsinto pages 1-2)

2) Current mechanistic understanding and pathways
- Complex composition and prerequisites: Human FTSJ1–WDR6 reconstitutes robust 2′-O-methylation in vitro and specifically catalyzes Nm34 on select tRNAs. Catalysis requires prior m1G37 formation (i.e., m1G37 is a prerequisite), and anticodon-loop modifications at positions 32, 34, and 37 show hierarchical interdependence in vivo (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2)
- Site specificity by partner switching: Partner selection dictates site specificity—WDR6 directs FTSJ1 to Nm34, whereas THADA directs FTSJ1 to Nm32—consistent with the division of labor model in multimeric RNA methyltransferases (WIREs RNA, May 2022; https://doi.org/10.1002/wrna.1673; 2023 review excerpt). (graille2022divisionoflabor pages 25-28, brazane2023functionsofthe pages 49-54)
- Structural logic from orthologs: Structural work on yeast Trm7–Trm734 shows how a WD40 subunit (Trm734) positions the anticodon loop at the catalytic center of Trm7; mutational analysis places functionally critical Trm734 residues near the Trm7 active site and supports a role in tRNA binding/positioning rather than complex assembly per se (ACS Omega, Jun 2024; DOI: 10.1021/acsomega.4c02313; https://doi.org/10.1021/acsomega.4c02313). These insights are directly informative for human WDR6 function. (funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10)
- Partner-specific substrate engagement: Cryo-EM of the human FTSJ1–THADA complex reveals a THADA scaffold that encloses tRNA and anchors its anticodon loop to FTSJ1’s catalytic pocket, illustrating how the noncatalytic subunit choreographs tRNA recognition; by analogy, WDR6 is expected to play the analogous role in the FTSJ1–WDR6 Nm34 holoenzyme (Communications Biology, Jun 2025; https://doi.org/10.1038/s42003-025-08278-3). (ishiguro2025structuralinsightsinto pages 1-2)

3) Substrate specificity and biochemical activity
- Human substrates and differences to yeast: The human FTSJ1–WDR6 complex generates Gm34 on specific cytosolic tRNAs including tRNAPhe(GAA) and tRNALeu(CAA), and displays substrate selectivity distinct from yeast Trm7–Trm734 (e.g., some yeast targets such as tRNATrp(CCA) are not modified by the human complex) (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)
- Hierarchical modification circuit: In vivo, Nm34 deposition is interdependent with Nm32 and m1G37 on the same tRNA species, indicating a conserved modification circuit at the anticodon loop that influences translation fidelity/efficiency (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095; WIREs RNA, May 2022; https://doi.org/10.1002/wrna.1673). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2, graille2022divisionoflabor pages 25-28)

4) Subcellular localization
- Direct subcellular localization of human WDR6 in the context of FTSJ1-mediated tRNA methylation is not explicitly specified in the cited experimental sources; however, these tRNA modifications are canonical cytosolic tRNA anticodon-loop marks, and the yeast Trm7–Trm734 model supports a cytosolic/nucleocytoplasmic tRNA-processing context. More precise human localization will require targeted proteomic/cell-biological studies; such data were not provided in the reviewed sources. (graille2022divisionoflabor pages 25-28, li2020intellectualdisability‐associatedgene pages 9-11)

5) Functional consequences and phenotypes
- Codon-specific translational effects: FTSJ1 deficiency reduces translation efficiency of UUU (but not UUC) phenylalanine codons due to loss of Gm34/Cm32 on tRNAPhe(GAA); overexpression of tRNAPhe(GAA) can rescue growth defects in cellular models (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2)
- Gene set enrichment: Approximately 40% of genes with high TTT codon usage bias (decoded by UUU) are nervous system–related, linking defective FTSJ1-mediated methylation to neuronal gene expression programs (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)
- Regulatory-subunit roles inferred from yeast: Mutational dissection of yeast Trm734 identifies residues essential for Nm34 formation that are dispensable for Trm7–Trm734 binding; such separation-of-function variants provide tools to parse tRNA-modification–dependent versus –independent phenotypes, a strategy likely transferrable to human WDR6 studies (ACS Omega, Jun 2024; https://doi.org/10.1021/acsomega.4c02313). (funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10)

6) Disease associations and expert perspectives
- NSXLID and FTSJ1: Human FTSJ1 loss-of-function alleles cause loss of Cm32/Gm34 on tRNAPhe(GAA) and are implicated in nonsyndromic X-linked intellectual disability; the dependence of Nm34 on the WDR6 partner rationalizes WDR6’s centrality for the Nm34 arm of this pathway (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095; WIREs RNA, May 2022; https://doi.org/10.1002/wrna.1673). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2, graille2022divisionoflabor pages 25-28)
- Expert analysis on multimeric methyltransferases: Reviews emphasize a division-of-labor paradigm in which WD40 partners scaffold and orient tRNA substrates to a Rossmann-fold catalytic subunit, consistent with WDR6’s proposed role in the FTSJ1 holoenzyme (WIREs RNA, May 2022; https://doi.org/10.1002/wrna.1673; 2023 review excerpt). (graille2022divisionoflabor pages 25-28, brazane2023functionsofthe pages 49-54)

7) Recent developments (priority 2023–2024)
- 2024 mechanistic advances: Yeast Trm734 mutational mapping (ACS Omega, Jun 2024) pinpoints tRNA-interacting surfaces critical for Nm34 and suggests design of nonfunctional yet stable Trm734 variants; these principles likely guide human WDR6 functional mapping and the creation of separation-of-function alleles for mechanistic and disease-modeling studies (https://doi.org/10.1021/acsomega.4c02313). (funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10)
- 2023 synthesis: A 2023 review highlights that human FTSJ1 leverages distinct partners—THADA for Nm32 and WDR6 for Nm34—to achieve site specificity, integrating structural insights from yeast holoenzymes and underscoring neurological implications (review excerpt). (brazane2023functionsofthe pages 49-54)
- 2022–2025 structural framework: The 2022 WIREs RNA review consolidates structural lessons from multimeric RNA MTases, while the 2025 cryo-EM structure of human FTSJ1–THADA provides a direct human blueprint for partner-mediated tRNA engagement; together these frame hypotheses for WDR6’s structural role in Nm34 (https://doi.org/10.1002/wrna.1673; https://doi.org/10.1038/s42003-025-08278-3). (graille2022divisionoflabor pages 25-28, ishiguro2025structuralinsightsinto pages 1-2)

8) Applications and real-world implementations
- Molecular diagnostics/biomarkers: Loss of FTSJ1-dependent Nm modifications on tRNAPhe(GAA) provides a molecular signature that could be assayed in patient-derived cells to support NSXLID diagnoses and genotype–phenotype correlations; WDR6-dependent Nm34 may contribute to such readouts (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)
- Functional variant engineering: Guided by 2024 Trm734 mutational data, analogous WDR6 variants can be engineered to test whether neurological or other phenotypes arise specifically from loss of Nm34 versus potential noncanonical WDR6 roles, facilitating target validation and pathway dissection (ACS Omega, Jun 2024; https://doi.org/10.1021/acsomega.4c02313). (funk2024identificationofamino pages 7-7)
- Therapeutic hypothesis generation: Since reduced UUU translation contributes to dysregulation of TTT-biased neuronal genes when FTSJ1 function is compromised, interventions that restore tRNAPhe(GAA) function or mimic Nm34 could, in principle, ameliorate disease-relevant translational defects; such strategies remain to be experimentally validated (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)

9) Quantitative data and selected statistics
- Hierarchical modification: m1G37 is a prerequisite for FTSJ1–WDR6–mediated Nm34 in vitro; in vivo, positions 32, 34, 37 modifications are interdependent and ordered (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2)
- Codon translation impact: FTSJ1 knockout reduces translation efficiency for UUU but not UUC codons decoded by tRNAPhe(GAA), demonstrating codon-specific effects of anticodon-loop Nm loss (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)
- Nervous system gene bias: Approximately 40% of TTT-biased genes are related to brain/nervous system functions, connecting the translational phenotype to neuronal pathways (EMBO Reports, Jun 2020; https://doi.org/10.15252/embr.202050095). (li2020intellectualdisability‐associatedgene pages 9-11)
- Structure–function residues (ortholog evidence): Trm734 residues proximal to the Trm7 active site are essential for Nm34 formation but dispensable for complex assembly, consistent with a substrate-docking role (ACS Omega, Jun 2024; https://doi.org/10.1021/acsomega.4c02313). (funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10)

10) Knowledge gaps and future directions
- Direct human FTSJ1–WDR6 structural biology: High-resolution structures of human FTSJ1–WDR6 (± tRNA) are needed to define WDR6’s tRNA-docking surfaces and partner interfaces; the THADA structure provides a compelling template for experimental design (Communications Biology, Jun 2025; https://doi.org/10.1038/s42003-025-08278-3). (ishiguro2025structuralinsightsinto pages 1-2)
- Subcellular localization and dynamics: Definitive localization of WDR6 in the context of tRNA modification, its cell-cycle dynamics, and interaction proteome in human cells remain to be clarified in targeted studies (current sources do not specify). (graille2022divisionoflabor pages 25-28, li2020intellectualdisability‐associatedgene pages 9-11)
- Disease genetics for WDR6: While FTSJ1 variants are clearly implicated in NSXLID, the specific contribution of WDR6 variants to human disease via loss of Nm34 has yet to be systematically defined; separation-of-function alleles informed by ortholog studies can address this (ACS Omega, Jun 2024; https://doi.org/10.1021/acsomega.4c02313). (funk2024identificationofamino pages 7-7)

References with URLs and dates (supporting citations use context IDs above)
- Li J et al. Intellectual disability–associated gene FTSJ1 is responsible for 2′-O-methylation of specific tRNAs. EMBO Reports. Published Jun 2020. URL: https://doi.org/10.15252/embr.202050095 (li2020intellectualdisability‐associatedgene pages 9-11, li2020intellectualdisability‐associatedgene pages 1-2)
- Funk HM et al. Identification of amino acids in Trm734 required for 2′-O-methylation of the tRNAPhe wobble residue. ACS Omega. Published Jun 2024. URL: https://doi.org/10.1021/acsomega.4c02313 (funk2024identificationofamino pages 7-7, funk2024identificationofamino pages 9-10)
- Graille M. Division of labor in epitranscriptomics: What have we learnt from the structures of eukaryotic and viral multimeric RNA methyltransferases? WIREs RNA. Published May 2022. URL: https://doi.org/10.1002/wrna.1673 (graille2022divisionoflabor pages 25-28)
- Brazane M. Functions of the ribose methyltransferase FTSJ1 in regulation of gene expression and neural development. 2023 review excerpt (publication details not specified in excerpt). (brazane2023functionsofthe pages 49-54)
- Ishiguro K et al. Structural insights into tRNA recognition of the human FTSJ1–THADA complex. Communications Biology. Published Jun 2025. URL: https://doi.org/10.1038/s42003-025-08278-3 (used here as structural contrast for partner-mediated specificity) (ishiguro2025structuralinsightsinto pages 1-2)

Mandatory verification summary
- Symbol match and organism: WDR6 (human) matches UniProt Q9NNW5, WD repeat family; literature consistently identifies WDR6 as the human Trm734 ortholog partnering with FTSJ1 for Nm34 on tRNAs (WIREs RNA 2022; EMBO Reports 2020). (graille2022divisionoflabor pages 25-28, li2020intellectualdisability‐associatedgene pages 9-11)
- Family/domains: WD40/β-propeller regulatory role for substrate docking in multimeric RNA methyltransferases is consistent with WDR6’s proposed function (WIREs RNA 2022). (graille2022divisionoflabor pages 25-28)
- Ambiguity check: No conflicting gene symbol usage or nonhuman conflation was identified in the cited sources. (graille2022divisionoflabor pages 25-28, li2020intellectualdisability‐associatedgene pages 9-11)

References

1. (li2020intellectualdisability‐associatedgene pages 9-11): Jing Li, Yan‐Nan Wang, Bei‐Si Xu, Ya‐Ping Liu, Mi Zhou, Tao Long, Hao Li, Han Dong, Yan Nie, Peng R Chen, En‐Duo Wang, and Ru‐Juan Liu. Intellectual disability‐associated gene ftsj1 is responsible for 2′‐o‐methylation of specific trnas. EMBO Reports, Jun 2020. URL: https://doi.org/10.15252/embr.202050095, doi:10.15252/embr.202050095. This article has 59 citations and is from a highest quality peer-reviewed journal.

2. (li2020intellectualdisability‐associatedgene pages 1-2): Jing Li, Yan‐Nan Wang, Bei‐Si Xu, Ya‐Ping Liu, Mi Zhou, Tao Long, Hao Li, Han Dong, Yan Nie, Peng R Chen, En‐Duo Wang, and Ru‐Juan Liu. Intellectual disability‐associated gene ftsj1 is responsible for 2′‐o‐methylation of specific trnas. EMBO Reports, Jun 2020. URL: https://doi.org/10.15252/embr.202050095, doi:10.15252/embr.202050095. This article has 59 citations and is from a highest quality peer-reviewed journal.

3. (graille2022divisionoflabor pages 25-28): Marc Graille. Division of labor in epitranscriptomics: what have we learnt from the structures of eukaryotic and viral multimeric rna methyltransferases? Wiley Interdisciplinary Reviews: RNA, May 2022. URL: https://doi.org/10.1002/wrna.1673, doi:10.1002/wrna.1673. This article has 9 citations.

4. (brazane2023functionsofthe pages 49-54): M Brazane. Functions of the ribose methyltransferase ftsj1 in regulation of gene expression and neural development. Unknown journal, 2023.

5. (funk2024identificationofamino pages 7-7): Holly M. Funk, Jennifer H. Brooks, Alisha E. Detmer, Natalie N. Creech, and Michael P. Guy. Identification of amino acids in trm734 required for 2′-o-methylation of the trna^phe wobble residue. ACS Omega, 9:25063-25072, Jun 2024. URL: https://doi.org/10.1021/acsomega.4c02313, doi:10.1021/acsomega.4c02313. This article has 0 citations and is from a peer-reviewed journal.

6. (funk2024identificationofamino pages 9-10): Holly M. Funk, Jennifer H. Brooks, Alisha E. Detmer, Natalie N. Creech, and Michael P. Guy. Identification of amino acids in trm734 required for 2′-o-methylation of the trna^phe wobble residue. ACS Omega, 9:25063-25072, Jun 2024. URL: https://doi.org/10.1021/acsomega.4c02313, doi:10.1021/acsomega.4c02313. This article has 0 citations and is from a peer-reviewed journal.

7. (ishiguro2025structuralinsightsinto pages 1-2): Kensuke Ishiguro, Atsushi Fujimura, and Mikako Shirouzu. Structural insights into trna recognition of the human ftsj1-thada complex. Communications Biology, Jun 2025. URL: https://doi.org/10.1038/s42003-025-08278-3, doi:10.1038/s42003-025-08278-3. This article has 2 citations and is from a peer-reviewed journal.

Citations

1. graille2022divisionoflabor pages 25-28
2. ishiguro2025structuralinsightsinto pages 1-2
3. brazane2023functionsofthe pages 49-54
4. funk2024identificationofamino pages 7-7
5. funk2024identificationofamino pages 9-10
6. https://doi.org/10.1002/wrna.1673
7. https://doi.org/10.15252/embr.202050095
8. https://doi.org/10.1038/s42003-025-08278-3
9. https://doi.org/10.1002/wrna.1673;
10. https://doi.org/10.1021/acsomega.4c02313
11. https://doi.org/10.15252/embr.202050095;
12. https://doi.org/10.15252/embr.202050095,
13. https://doi.org/10.1002/wrna.1673,
14. https://doi.org/10.1021/acsomega.4c02313,
15. https://doi.org/10.1038/s42003-025-08278-3,

WD Repeat Domain 6 (WDR6) – Structure, Function, and Biological Roles

Introduction and Key Characteristics

WDR6 (WD repeat domain 6) is a human protein encoded by the WDR6 gene, belonging to the WD-repeat protein family. WD-repeat proteins are defined by repeating ~40–60 amino acid motifs typically ending in a tryptophan-aspartate (W-D) dipeptide (pmc.ncbi.nlm.nih.gov). These repeats fold into β-propeller structures that serve as scaffolds for protein–protein interactions, enabling assembly of multi-protein complexes (pmc.ncbi.nlm.nih.gov). Consistent with this role, WDR6 is composed of 11 WD-repeat units and is ~1121 amino acids in length (pubmed.ncbi.nlm.nih.gov). Notably, the repeats of WDR6 are arranged in two clusters separated by a hydrophobic segment that was initially predicted as a transmembrane region (pubmed.ncbi.nlm.nih.gov). Despite this predicted domain, experiments indicate WDR6 is predominantly an intracellular protein localized to the cytoplasm, similar to its interaction partner LKB1 (pubmed.ncbi.nlm.nih.gov). Early northern blot analyses showed WDR6 is ubiquitously expressed in adult and fetal human tissues (pubmed.ncbi.nlm.nih.gov), suggesting it serves fundamental cellular functions. Indeed, WDR6 has emerged as a multifaceted regulatory adaptor protein implicated in diverse processes including RNA modification, cell cycle control, metabolism, and intracellular signaling.

Structurally, WDR6 is a member of a highly conserved subfamily of WD proteins. It shows homology to yeast proteins like Trm734, a factor required for tRNA modification (pubmed.ncbi.nlm.nih.gov). In fact, WDR6 is the human homolog of yeast Trm734, which foreshadows one of WDR6’s key roles in RNA biology. No close paralogs of WDR6 exist in humans beyond the general WD-repeat motif (WDR1–WDR5 are distinct proteins) (pubmed.ncbi.nlm.nih.gov). The WD β-propeller domain of WDR6 (InterPro: IPR015943) suggests it provides a platform for binding other macromolecules, consistent with WDR6’s role in multi-protein complexes. Below, we discuss the current understanding of WDR6’s functions, drawing on recent research (primarily 2020–2023) and how this protein contributes to specific biochemical pathways, cellular localization of its activity, and potential real-world applications.

Role in tRNA Anticodon Loop Modification and Translation

One well-characterized function of WDR6 is as a co-factor in tRNA modification. WDR6 is annotated as a “tRNA (34-2'-O)-methyltransferase regulator,” referring to position 34 in the tRNA anticodon loop (www.ncbi.nlm.nih.gov) (pubchem.ncbi.nlm.nih.gov). Specifically, WDR6 associates with the methyltransferase enzyme FTSJ1 (also known as Trm7 in other organisms) to catalyze 2′-O-methylation of ribose at the wobble position (nucleotide 34) of specific tRNAs (pmc.ncbi.nlm.nih.gov). FTSJ1 is an S-adenosylmethionine-dependent methyltransferase, and WDR6 serves as an essential auxiliary subunit for its activity (pmc.ncbi.nlm.nih.gov). A 2020 study by Li et al. reconstituted the human FTSJ1–WDR6 complex in vitro and demonstrated that it methylates the 2’-OH of nucleotide 34 (forming Cm34 or Gm34) on target tRNAs (pmc.ncbi.nlm.nih.gov). This modification occurs only on tRNAs that also carry a methylated guanosine at position 37 (m¹G37), indicating that WDR6–FTSJ1-mediated 2′-O-methylation at position 34 is tightly linked to other anticodon-loop modifications (pmc.ncbi.nlm.nih.gov). In cells lacking functional FTSJ1 (such as patient cells with FTSJ1 mutations), certain tRNAs – for example, tRNA^Phe(GAA) – were found to completely lack 2′-O-methylation at C32 and G34 (pmc.ncbi.nlm.nih.gov). This corresponds to the yeast paradigm where Trm7 (FTSJ1 homolog) requires two accessory proteins (Trm732 and Trm734) to modify positions 32 and 34, respectively (pubmed.ncbi.nlm.nih.gov). WDR6 is the higher eukaryote homolog of yeast Trm734, the factor specifically needed for the position 34 modification (pubmed.ncbi.nlm.nih.gov). Consistently, WDR6 is required for proper positioning of the tRNA substrate in the FTSJ1 active site and for full methyltransferase activity (www.genecards.org).

Functionally, these tRNA modifications are critical for accurate decoding during protein synthesis. The anticodon-loop 2′-O-methylations enhance tRNA structure and ribosome binding, thereby influencing translational fidelity and efficiency (pmc.ncbi.nlm.nih.gov). In humans, loss of the FTSJ1/WDR6-mediated modifications has been linked to disease: mutations in FTSJ1 (an X-linked gene) cause a form of non-syndromic intellectual disability, presumably due to downstream effects on protein synthesis in neurons (pubmed.ncbi.nlm.nih.gov). While germline mutations in WDR6 itself have not been reported in this disorder, the requirement of WDR6 for FTSJ1 activity suggests that WDR6 is crucial for the biogenesis of properly modified tRNAs, especially in the brain. Indeed, one analysis found that ~40% of the genes with a strong codon bias for UUU (phenylalanine codon decoded by tRNA^Phe) are related to brain and nervous system functions (pmc.ncbi.nlm.nih.gov). This underscores the idea that WDR6, by enabling specific tRNA modifications, indirectly supports the translation of mRNAs vital for neural development and function.

At the cellular level, WDR6 and FTSJ1 are cytoplasmic enzymes (pmc.ncbi.nlm.nih.gov), acting on cytosolic tRNA pools. WDR6 does not itself catalyze methylation (it lacks a catalytic domain), but serves as a scaffold or guide – likely binding the tRNA and/or the FTSJ1 enzyme – to ensure the correct tRNA conformation for methyl transfer (www.genecards.org). This has parallels to other tRNA-modifying complexes (e.g., the METTL1–WDR4 complex for tRNA m^7G46, where WDR4 is a non-catalytic WD-repeat subunit that orientates the tRNA) (www.ncbi.nlm.nih.gov) (www.nature.com). In summary, WDR6’s primary biochemical function identified so far is in the tRNA epitranscriptomic pathway: it partners with the FTSJ1 methyltransferase to modify the anticodon loop, thereby safeguarding translational accuracy. This role is supported by strong experimental evidence (pmc.ncbi.nlm.nih.gov) and highlights WDR6’s broader theme of action – acting as a non-enzymatic regulator within larger protein complexes.

Interaction with LKB1 and Cell Cycle Regulation

Beyond RNA biology, WDR6 has been linked to tumor suppressor signaling and cell cycle control. In a yeast two-hybrid screen reported in 2007, WDR6 was identified as a binding partner of the serine/threonine kinase LKB1 (also known as STK11) (pubmed.ncbi.nlm.nih.gov). LKB1 is a master kinase that activates AMP-activated protein kinase (AMPK) and other kinases, and germline LKB1 mutations cause Peutz-Jeghers cancer syndrome. The WDR6–LKB1 interaction is cytoplasmic (both proteins colocalize in the cytosol (pubmed.ncbi.nlm.nih.gov)), and functionally WDR6 appears to enhance LKB1’s growth-inhibitory effects. Co-expression of WDR6 with LKB1 in cell culture significantly increased LKB1’s ability to arrest cell proliferation and induce a G₁ cell-cycle block (pubmed.ncbi.nlm.nih.gov). In these experiments, WDR6 synergized with LKB1 to elevate levels of the CDK inhibitor p27^Kip1, a key enforcer of the G₁ checkpoint (pubmed.ncbi.nlm.nih.gov). Reporter assays showed that WDR6 boosted LKB1-dependent transcription from the p27^Kip1 promoter, suggesting WDR6 helps transmit LKB1’s signal to cell cycle regulatory genes (pubmed.ncbi.nlm.nih.gov).

Collectively, these findings provide initial evidence that WDR6 participates in the LKB1 tumor-suppressor pathway (pubmed.ncbi.nlm.nih.gov). Specifically, WDR6 acts as a positive regulator or co-factor of LKB1, aiding it to induce cell-cycle arrest and growth suppression (pubmed.ncbi.nlm.nih.gov). The mechanism is not fully determined, but given LKB1’s role in activating AMPK and related kinases, one hypothesis is that WDR6 might anchor LKB1 near specific substrates or assist in assembling complexes (for example, linking LKB1 to transcriptional co-regulators of the p27 gene) (pubmed.ncbi.nlm.nih.gov). Notably, LKB1 also influences cellular metabolism and polarity; whether WDR6 contributes to those aspects is not yet clear. Importantly, from a functional annotation perspective, this interaction positions WDR6 in a cellular stress and growth checkpoint pathway. It also connects WDR6 to cancer biology: loss of LKB1 is common in lung adenocarcinoma and other cancers, and WDR6’s ability to augment LKB1’s function suggests it may have tumor-suppressive effects when LKB1 is present (pubmed.ncbi.nlm.nih.gov). Indeed, the RefSeq gene summary (2016) for WDR6 highlights that WDR6 is “implicated in cell growth arrest” via its interaction with LKB1 (www.genecards.org). This role exemplifies WDR6 functioning as an adapter protein in signaling pathways – in this case, linking a kinase (LKB1) to the cell cycle machinery.

Involvement in Autophagy and Nutrient Signaling

Another emerging role for WDR6 is in autophagy regulation, particularly during nutrient stress. Evidence for this came from a genetic screening study in 2012 that pointed to WDR6 as a factor in starvation-induced autophagy (pmc.ncbi.nlm.nih.gov). Autophagy is a catabolic process activated during amino acid starvation to recycle nutrients, and its regulation involves nutrient-sensing pathways (e.g. mTOR and AMPK). WDR6 has been reported as necessary to suppress autophagy when cells are starved for amino acids (www.genecards.org). In other words, in the absence of WDR6, cells may undergo heightened autophagy upon nutrient deprivation. This was initially a somewhat counterintuitive finding – since starvation normally induces autophagy – but it suggests WDR6 might normally act to fine-tune or limit the autophagic response (pmc.ncbi.nlm.nih.gov). One possibility is that WDR6 interfaces with the AMPK–mTOR pathway (LKB1 is an upstream kinase for AMPK, and AMPK activation promotes autophagy). The WDR6–LKB1 connection hints that WDR6 could modulate AMPK or mTOR signaling, thereby affecting autophagy induction (pmc.ncbi.nlm.nih.gov). In support of this notion, WDR6 was found to co-immunoprecipitate with LKB1 (upstream of AMPK) and to appear in an autophagy-focused interaction screen, although those reports did not fully clarify the mechanism (pmc.ncbi.nlm.nih.gov).

Recent research has provided more direct insight into how WDR6 can regulate autophagy and how this ties into disease contexts. A 2023 study in EMBO Molecular Medicine examined WDR6’s function in liver cancer and uncovered a mechanism connecting WDR6 to the autophagy machinery (pmc.ncbi.nlm.nih.gov). The authors found that WDR6 binds to UVRAG (UV radiation resistance-associated gene protein), which is a key component of the autophagy initiation complex (part of the Beclin1-PI3KC3/Vps34 pathway). WDR6 targets UVRAG for degradation by recruiting it to a Cullin-4A E3 ubiquitin ligase complex (CUL4A–DDB1–ROC1) (pmc.ncbi.nlm.nih.gov). WDR6 contains a unique “WDxR” motif – a short sequence within a WD-repeat blade – that mediates this recruitment to the E3 ligase (pmc.ncbi.nlm.nih.gov). Through this mechanism, WDR6 promotes UVRAG’s ubiquitination and proteolysis, effectively blunting autophagy initiation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consequences of UVRAG loss were observed as an accumulation of the transcription factor NF-κB p65, which under normal conditions can be degraded via autophagy (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In WDR6-proficient cells, UVRAG is degraded, autophagic turnover of p65 is blocked, and NF-κB (p65) remains active, driving robust production of TNFα (tumor necrosis factor) (pmc.ncbi.nlm.nih.gov). Thus, WDR6 creates a link between autophagy and inflammatory signaling: by suppressing autophagic clearance of p65, it sustains NF-κB/TNFα signaling.

This WDR6-NF-κB connection has significant effects on the immune environment, especially in tumors (detailed in the next section). From a cell biology standpoint, it solidifies WDR6’s role as a regulator of autophagy and stress responses. WDR6’s inhibition of autophagy (via UVRAG degradation) aligns with earlier observations that WDR6 is required to suppress autophagy during starvation (www.genecards.org). It appears WDR6 might ensure that autophagy doesn’t overshoot or that certain autophagy-related proteins are kept in check. The discovery of the WDxR motif as a functional element also suggests WDR6 may belong to a class of DDB1–CUL4-associated factors (DCAFs) – substrate adaptors that present specific targets (like UVRAG) to the CUL4 E3 ubiquitin ligase (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Indeed, other WD-repeat proteins are known to serve as substrate receptors for CUL4-based E3 complexes (pmc.ncbi.nlm.nih.gov), and WDR6 now appears to be one of them.

In summary, WDR6 modulates autophagy by controlling the stability of an autophagy initiator (UVRAG). This places WDR6 at a crossroads between nutrient-sensing pathways, autophagic flux, and inflammatory signaling. The autophagy-suppressing function of WDR6 could have broad implications: excessive or dysregulated autophagy is involved in neurodegeneration and cancer; WDR6 might normally help restrain autophagy to balanced levels, though in pathological contexts this restraint can be double-edged (as discussed below for tumors). These insights, mostly uncovered in the last few years, highlight WDR6’s expanding functional repertoire beyond its original identification as a tRNA methylation cofactor.

Metabolic Functions in Insulin Signaling and Lipogenesis

Emerging evidence indicates that WDR6 also plays a role in metabolic regulation, particularly in the context of insulin signaling and lipid metabolism. A 2023 study in Nature Metabolism found that WDR6 is upregulated in the livers of insulin-resistant mice and drives hepatic de novo lipogenesis (DNL) – the synthesis of fatty acids in the liver (www.nature.com). Under normal physiology, insulin promotes lipogenesis via transcription factors like SREBP1c. In insulin resistance (IR), certain insulin signals fail (e.g. glucose uptake), but paradoxically the lipogenic pathway often remains active, contributing to fatty liver (hepatic steatosis) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Investigating this phenomenon, researchers discovered that WDR6 levels increase in the liver during high-fat-diet induced insulin resistance, and that WDR6 is required for the continued activation of lipogenic gene expression in this state (pmc.ncbi.nlm.nih.gov).

Mechanistically, WDR6 was shown to bind the β-catalytic subunit of protein phosphatase 1 (PPP1CB) (www.nature.com). Protein phosphatase-1 is a key serine/threonine phosphatase whose activity can be modulated by regulatory subunits. WDR6 appears to function as a targeting/regulatory subunit for PP1β. Specifically, WDR6 binding facilitates dephosphorylation of PP1β at Thr316 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Dephosphorylation at this site is thought to enhance PP1β activity (Thr316 phosphorylation can negatively regulate PP1 activity (pmc.ncbi.nlm.nih.gov)). Active PP1β, in turn, was found to influence a signaling axis involving DNA-dependent protein kinase (DNA-PK) and the transcription factor USF1 (pmc.ncbi.nlm.nih.gov) (www.nature.com). The outcome of this cascade is increased transcription of FASN, the gene encoding fatty acid synthase, which is a rate-limiting enzyme in fatty acid production (pmc.ncbi.nlm.nih.gov) (www.nature.com). In WDR6 knockout liver cells, FASN expression was significantly reduced, confirming WDR6’s role in upregulating lipogenic enzymes (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Conversely, expressing a mutant PP1β that mimics the dephosphorylated state (Thr316Ala) elevated FASN levels, whereas a phosphomimetic PP1β (Thr316Asp) depressed FASN, matching the effect of WDR6 on PP1β regulation (pmc.ncbi.nlm.nih.gov). These findings suggest that WDR6 promotes lipogenesis by activating PP1β, which then triggers a pro-lipogenic gene transcription program (pmc.ncbi.nlm.nih.gov).

Importantly, this study also demonstrated a potential therapeutic angle: using molecular modeling and screening, the authors identified a small natural compound (referred to as XLIX) that disrupts the WDR6–PPP1CB interaction, thereby keeping PP1β in a phosphorylated (less active) state (www.nature.com). Treatment with this compound in insulin-resistant mice reduced hepatic FASN expression and lipid accumulation, effectively mitigating fatty liver development (www.nature.com). This proof-of-concept highlights WDR6 as a promising drug target for metabolic diseases like non-alcoholic fatty liver disease (NAFLD) associated with insulin resistance (www.nature.com). In summary, WDR6 has a critical role in a novel insulin-regulated pathway: by acting as a PP1 regulatory subunit, it connects insulin signaling to the control of a major metabolic enzyme. This function again reflects WDR6’s general theme of action as a scaffold protein – here, bringing together a phosphatase (PP1β) with its target pathways to modulate phosphorylation-dependent signals.

It is intriguing that WDR6 interacts with an insulin receptor substrate in other contexts as well. An earlier proteomics study in rat brain found WDR6 as a binding partner of IRS4 (insulin receptor substrate-4) (www.ncbi.nlm.nih.gov), which may hint at additional links between WDR6 and insulin/IGF signaling pathways. While the full scope of WDR6’s metabolic involvement is not yet known, the current data firmly establish WDR6 as an insulin-responsive regulator of lipid metabolism. Given the rise in metabolic syndrome and NAFLD cases, the discovery of WDR6’s role in lipogenesis is a significant development that occurred in 2023. It provides a specific biochemical function (regulation of PP1β activity) for WDR6 in the metabolic context, expanding the protein’s functional annotation.

Implications in Cancer and Immunology

Considering WDR6’s roles in cell growth (LKB1 pathway), autophagy, and metabolism, it is perhaps not surprising that dysregulation of WDR6 has been linked to cancer. However, until recently WDR6 was a relatively little-explored gene in oncology (pmc.ncbi.nlm.nih.gov). New research has begun to clarify WDR6’s impact on tumor biology and the tumor immune microenvironment. The 2023 EMBO Molecular Medicine study on hepatocellular carcinoma (HCC) is particularly illuminating. This study found that WDR6 promotes an immunosuppressive, tumor-promoting microenvironment in HCC (pmc.ncbi.nlm.nih.gov). In a series of experiments, the authors showed that knocking out WDR6 in mouse HCC cells had minimal effect on their growth in vitro, but drastically inhibited tumor growth and lung metastasis in vivo when these cells were implanted into immune-competent mice (pmc.ncbi.nlm.nih.gov). In immune-deficient mice, WDR6 status had little impact on tumor growth (pmc.ncbi.nlm.nih.gov), indicating that WDR6’s pro-tumor effects are largely mediated through the immune system rather than cell-intrinsic proliferation.

Mechanistically, as discussed, WDR6 drives NF-κB/TNFα signaling by blocking autophagic degradation of p65 through UVRAG ubiquitination (pmc.ncbi.nlm.nih.gov). The consequence in tumors is that high WDR6 expression leads to chronically elevated TNFα levels, which reshape the immune cell population in the tumor (pmc.ncbi.nlm.nih.gov). TNFα is a cytokine that can recruit immunosuppressive myeloid cells. Indeed, WDR6-proficient HCC tumors had a higher infiltration of MDSCs (myeloid-derived suppressor cells) and a lower presence of activated CD8⁺ T cells (pmc.ncbi.nlm.nih.gov). MDSCs are known to suppress T-cell responses, and their accumulation creates a microenvironment conducive to tumor progression. The study demonstrated that these effects could be partly reversed by blocking TNFα – inhibiting TNFα signaling led to improved T-cell infiltration and tumor control in WDR6-high tumors (pmc.ncbi.nlm.nih.gov). Furthermore, TNFα itself was found to feed back and increase WDR6 transcription via NF-κB, establishing a vicious positive feedback loop (WDR6 → ↑TNFα → ↑WDR6) (pmc.ncbi.nlm.nih.gov). This loop helps explain how WDR6 may become upregulated in cancers and sustain an immunosuppressive niche. Clinically, analysis of HCC patient samples showed that the WDR6/UVRAG/NF-κB axis is hyperactivated in a subset of HCC and correlates with poor prognosis (pmc.ncbi.nlm.nih.gov). High WDR6 expression in tumors could therefore serve as a marker of aggressive disease.

Excitingly, the HCC study also provided a therapeutic proof-of-concept: a peptide that mimics the WDxR motif was used to disrupt the WDR6–UVRAG interaction, thereby preventing UVRAG degradation (pmc.ncbi.nlm.nih.gov). In preclinical models, this WDxR-mimetic peptide restored autophagy, reduced TNFα levels, and enhanced the efficacy of anti-PD-L1 immunotherapy against WDR6-driven tumors (pmc.ncbi.nlm.nih.gov). Anti-PD-L1 (checkpoint blockade) is more effective when immunosuppression in the tumor microenvironment is relieved, so breaking the WDR6-TNFα loop made the tumors more responsive. This finding suggests that WDR6 could be a novel immuno-oncology target: patients with WDR6-overexpressing tumors might benefit from therapies that inhibit WDR6 function or its downstream effects. This is a striking example of how deep functional research on a gene can directly inform potential translational strategies.

Apart from HCC, WDR6’s role in other cancers is also being investigated. A bioinformatics-driven study in 2022 analyzed WDR6 expression across cancers, with a focus on lung cancer. Interestingly, in contrast to HCC, higher WDR6 expression was associated with better survival in non-small cell lung cancer patients (pmc.ncbi.nlm.nih.gov). In lung adenocarcinoma (LUAD), WDR6 levels correlated positively with advanced tumor stage (higher in later stages) (pmc.ncbi.nlm.nih.gov), yet paradoxically patients with WDR6-high tumors had longer overall and relapse-free survival compared to WDR6-low patients (pmc.ncbi.nlm.nih.gov). The same study reported that WDR6 expression in lung cancer correlates with markers of immune infiltration – including levels of various lymphocytes, immunomodulatory genes, and chemokines (pmc.ncbi.nlm.nih.gov). One interpretation is that WDR6, being tied to immune pathways, might reflect an active immune environment in lung tumors that helps control the cancer (hence high WDR6 linking to better outcomes) (pmc.ncbi.nlm.nih.gov). This is somewhat at odds with the HCC findings (where WDR6 promoted an immune-suppressive environment), suggesting that WDR6’s impact may be context-dependent or differ by tissue. It’s possible that in lung cancers, WDR6’s association with LKB1 status is a factor – for instance, LKB1-inactivated lung tumors are known for poor immune surveillance, and if WDR6 requires LKB1 to execute certain functions, the net effect of WDR6 could differ. More research is needed to reconcile these observations. Nonetheless, the use of WDR6 as a prognostic biomarker has been proposed: one study concludes WDR6 could serve as a novel marker for survival and immune infiltration status in lung cancer (pmc.ncbi.nlm.nih.gov).

In summary, WDR6’s involvement in cancer spans multiple dimensions: cell-intrinsic roles (affecting cell cycle via p27 and metabolism via FASN) and cell-extrinsic roles (shaping the tumor immune microenvironment via NF-κB/TNFα and autophagy pathways). The current consensus is that WDR6, while not a classic oncogene or tumor suppressor by itself, functions as a modifier of signaling pathways that cancer cells hijack. Its ubiquitous expression and ability to interact with key players (kinases, phosphatases, ubiquitin ligases) put it in a position to modulate cancer-related phenotypes. As research from 2020–2023 has shown, WDR6 can both positively and negatively influence cancer progression, depending on the context, by rewiring metabolic and immune signals.

Conclusion and Future Perspectives

WDR6 is a prime example of a multi-functional scaffold protein whose importance has become clearer in recent years. Initially characterized simply as a novel WD-repeat protein with no known function, WDR6 is now recognized to play critical regulatory roles in:

• RNA biology: enabling specific tRNA base modifications and thus safeguarding translational fidelity (pmc.ncbi.nlm.nih.gov).
• Cell cycle control: partnering with the LKB1 kinase to induce cell-cycle arrest via p27^Kip1 (pubmed.ncbi.nlm.nih.gov).
• Autophagy and signaling: linking a ubiquitin ligase complex to an autophagy regulator (UVRAG), thereby modulating NF-κB activity and cytokine production (pmc.ncbi.nlm.nih.gov).
• Metabolism: acting as a PP1 phosphatase adaptor to boost lipogenic gene expression during insulin resistance (www.nature.com).

These diverse functions are unified by a theme: WDR6 serves as a molecular adaptor or co-factor, bringing enzymes or signaling molecules into the correct complexes or conformations to execute their functions. Through its WD-repeat domains, WDR6 can simultaneously bind multiple partners – a property that underlies its role in assembling the FTSJ1-tRNA complex, the LKB1 signaling complex, the PP1-DNA-PK-USF1 phosphatase complex, and the CUL4A-DDB1-UVRAG ubiquitin ligase complex. Its subcellular localization is mainly cytosolic (pubmed.ncbi.nlm.nih.gov), but it likely shuttles or localizes to where its partner proteins are (e.g., at the ribosome/tRNA interface, in the nucleus at gene promoters, or at autophagosome assembly sites) as needed.

From a functional annotation standpoint, WDR6 can be described as a scaffolding protein that regulates enzyme specificity and signal transduction. It has no known enzymatic activity of its own; instead, it confers substrate specificity or stability to enzymes like methyltransferases and phosphatases (www.genecards.org). Loss-of-function of WDR6 could thus have pleiotropic consequences, as seen in experimental models (e.g., impaired tRNA modification and codon translation, increased autophagy, reduced lipogenesis, and changes in cell cycle dynamics). However, because WDR6 is not absolutely essential for viability (mice and cells can survive without it, albeit with specific defects (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov)), its functions seem to fine-tune cellular processes rather than being wholly indispensable for basal survival.

In terms of real-world applications and ongoing research: WDR6 is gaining interest as a potential therapeutic target. The discovery of compounds and peptides that can inhibit WDR6 interactions (as shown for metabolic and cancer contexts) opens avenues for drug development (www.nature.com) (pmc.ncbi.nlm.nih.gov). For instance, a WDR6 inhibitor could be explored to treat fatty liver disease by reducing FASN-driven lipogenesis, or as an adjuvant in cancer immunotherapy to prevent WDR6-mediated immune evasion. Additionally, WDR6 expression levels might serve as biomarkers for certain diseases – high WDR6 could indicate a tRNA modification deficiency if FTSJ1 is mutated (helping in the diagnosis of related intellectual disability) or might inform prognosis and treatment choices in cancers (as suggested for lung cancer and HCC) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).

Going forward, there are still open questions. It will be important to delineate how WDR6 is regulated (what controls its expression and activity) and whether any post-translational modifications on WDR6 affect its function. Some data suggest WDR6 itself might be subject to regulation by major pathways (for example, NF-κB can induce WDR6, and insulin can upregulate WDR6) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Understanding these regulatory loops could provide further insight into how WDR6 integrates into cellular homeostasis. Moreover, the full set of WDR6-interacting proteins is likely broader than currently known; a systematic proteomic analysis could reveal additional partners and pathways involving WDR6.

In conclusion, WDR6 has evolved from an uncharacterized gene into a protein of significant interest due to its role in fundamental cellular processes and disease-related pathways. Its WD-repeat structure underpins versatile binding capabilities, allowing WDR6 to act as a critical node linking enzymes to their substrates or signaling molecules to their pathways. The latest research (2020–2024) has shed light on WDR6’s functions in tRNA modification, tumor suppression, autophagy, immunity, and metabolism, making it a compelling subject for further investigation in both basic biology and translational medicine (pmc.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov) (www.nature.com). As we continue to unravel WDR6’s interactome and regulatory mechanisms, we gain not only a deeper understanding of cellular complexity but also new strategies to combat diseases where WDR6’s pathways are dysregulated.

References: (Publication dates and sources for key studies)
- Li et al., 2020, EMBO Reports – Defined WDR6’s role with FTSJ1 in tRNA 2′-O-methylation (pmc.ncbi.nlm.nih.gov).
- Xie et al., 2007, Biochem. Biophys. Res. Commun. – Discovered WDR6’s interaction with LKB1 and effect on p27^Kip1 (pubmed.ncbi.nlm.nih.gov).
- McKnight et al., 2012, EMBO J. – Implicated WDR6 in amino-acid starvation induced autophagy (screening study) (pmc.ncbi.nlm.nih.gov).
- Zhang et al., 2023, EMBO Mol. Medicine – Elucidated WDR6–UVRAG–NFκB mechanism in HCC and immune evasion (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
- Meng et al., 2023, Nature Metabolism – Demonstrated WDR6’s role in insulin resistance and lipogenesis, and identified a WDR6-inhibiting compound (www.nature.com) (www.nature.com).
- Lv et al., 2022, Immun. Inflamm. Dis. – Correlated WDR6 expression with prognosis and immune infiltration in lung cancer (bioinformatics study) (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov).
- Bi et al., 2000, Biochem. Biophys. Res. Commun. – Cloned human WDR6, reported its sequence, chromosomal location, and ubiquitous expression (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov). (Foundational genomic data)

Citations

1. AnnotationURLCitation(end_index=537, start_index=363, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=WD%E2%80%90repeat%20protein%20is%20a%20conserved,repeat%20protein%20family%2C%20and%20this')
2. AnnotationURLCitation(end_index=863, start_index=689, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=WD%E2%80%90repeat%20protein%20is%20a%20conserved,repeat%20protein%20family%2C%20and%20this')
3. AnnotationURLCitation(end_index=1158, start_index=966, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=transduction%2C%20transcription%2C%20and%20proliferation,significant%20sequence%20similarity%20with%20Arabidopsis')
4. AnnotationURLCitation(end_index=1500, start_index=1308, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=transduction%2C%20transcription%2C%20and%20proliferation,significant%20sequence%20similarity%20with%20Arabidopsis')
5. AnnotationURLCitation(end_index=1805, start_index=1673, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=been%20fully%20elucidated,dependent%20kinase%20%28CDK')
6. AnnotationURLCitation(end_index=2058, start_index=1911, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=since%20its%2011%20WD%20repeats,probably%20belongs%20to%20a%20highly')
7. AnnotationURLCitation(end_index=2611, start_index=2479, title="Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32558197/#:~:text=Figure%20EV2,or%20Trm734%20from%20different%20species')
8. AnnotationURLCitation(end_index=2999, start_index=2838, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=fluorescence%20in%20situ%20hybridization,are%20its%20distantly%20related%20members')
9. AnnotationURLCitation(end_index=3820, start_index=3706, title='Wdr6 WD repeat domain 6 [Mus musculus (house mouse)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/83669#:~:text=...from%20OrthoDB%20,Go%20to%20the%20top')
10. AnnotationURLCitation(end_index=3914, start_index=3821, title="tRNA (34-2'-O)-methyltransferase regulator WDR6 (human) | Protein Target - PubChem", type='url_citation', url='https://pubchem.ncbi.nlm.nih.gov/protein/Q9NNW5#:~:text=website')
11. AnnotationURLCitation(end_index=4248, start_index=4126, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
12. AnnotationURLCitation(end_index=4501, start_index=4379, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
13. AnnotationURLCitation(end_index=4807, start_index=4685, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
14. AnnotationURLCitation(end_index=5161, start_index=5039, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
15. AnnotationURLCitation(end_index=5518, start_index=5350, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=tRNA%20modifications%20at%20the%20anti%E2%80%90codon,1%7DG37%20as%20a%20prerequisite')
16. AnnotationURLCitation(end_index=5818, start_index=5682, title="Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1 - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/26310293/#:~:text=Nonsyndromic%20X,FTSJ1%2C%20the%20likely%20TRM7%20homolog')
17. AnnotationURLCitation(end_index=6074, start_index=5942, title="Intellectual disability-associated gene ftsj1 is responsible for 2'-O-methylation of specific tRNAs - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/32558197/#:~:text=Figure%20EV2,or%20Trm734%20from%20different%20species')
18. AnnotationURLCitation(end_index=6368, start_index=6221, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=Together%20with%20methyltransferase%20FTSJ1%2C%20methylates,')
19. AnnotationURLCitation(end_index=6777, start_index=6611, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=We%20find%20that%20modifications%20at,FTSJ1%20and%20nervous%20system%20development')
20. AnnotationURLCitation(end_index=7164, start_index=7028, title="Defects in tRNA Anticodon Loop 2'-O-Methylation Are Implicated in Nonsyndromic X-Linked Intellectual Disability due to Mutations in FTSJ1 - PubMed", type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/26310293/#:~:text=Nonsyndromic%20X,FTSJ1%2C%20the%20likely%20TRM7%20homolog')
21. AnnotationURLCitation(end_index=7739, start_index=7573, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=We%20find%20that%20modifications%20at,FTSJ1%20and%20nervous%20system%20development')
22. AnnotationURLCitation(end_index=8153, start_index=7978, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=FTSJ1%2C%20an%20intellectual%20disability%20associated,UUU%20codon%20usage%20biased%20genes')
23. AnnotationURLCitation(end_index=8557, start_index=8410, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=Together%20with%20methyltransferase%20FTSJ1%2C%20methylates,')
24. AnnotationURLCitation(end_index=8868, start_index=8734, title='Wdr6 WD repeat domain 6 [Rattus norvegicus (Norway rat)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/301007#:~:text=NCBI%20www.ncbi.nlm.nih.gov%20%20...GeneRIF%20,Norway%20rat')
25. AnnotationURLCitation(end_index=8996, start_index=8869, title='Structures and mechanisms of tRNA methylation by METTL1–WDR4 | Nature', type='url_citation', url='https://www.nature.com/articles/s41586-022-05565-5#:~:text=Nature%20www,Thus%2C%20our%20structural%20models')
26. AnnotationURLCitation(end_index=9411, start_index=9289, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
27. AnnotationURLCitation(end_index=9974, start_index=9830, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Germline%20mutations%20of%20the%20serine%2Fthreonine,Consistently')
28. AnnotationURLCitation(end_index=10355, start_index=10223, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=been%20fully%20elucidated,dependent%20kinase%20%28CDK')
29. AnnotationURLCitation(end_index=10754, start_index=10586, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
30. AnnotationURLCitation(end_index=11015, start_index=10893, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=colony%20formation%20of%20Hela%20cells,Kip1')
31. AnnotationURLCitation(end_index=11309, start_index=11191, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=WDR6%20was%20able%20to%20synergize,Kip1')
32. AnnotationURLCitation(end_index=11546, start_index=11428, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=WDR6%20was%20able%20to%20synergize,Kip1')
33. AnnotationURLCitation(end_index=11851, start_index=11683, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
34. AnnotationURLCitation(end_index=12304, start_index=12136, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
35. AnnotationURLCitation(end_index=12961, start_index=12793, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
36. AnnotationURLCitation(end_index=13230, start_index=13104, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=,provided%20by%20RefSeq%2C%20Feb%202016')
37. AnnotationURLCitation(end_index=13836, start_index=13669, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=match%20at%20L830%20screening%20suggesting,WDR6%20in%20autophagy%2C%20these%20data')
38. AnnotationURLCitation(end_index=14239, start_index=14109, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=the%20substrate%20tRNA%20for%20methylation,')
39. AnnotationURLCitation(end_index=14707, start_index=14538, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=screening%20suggesting%20a%20possible%20role,WDR6%20in%20autophagy%2C%20these%20data')
40. AnnotationURLCitation(end_index=15142, start_index=14973, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=screening%20suggesting%20a%20possible%20role,WDR6%20in%20autophagy%2C%20these%20data')
41. AnnotationURLCitation(end_index=15525, start_index=15356, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=screening%20suggesting%20a%20possible%20role,WDR6%20in%20autophagy%2C%20these%20data')
42. AnnotationURLCitation(end_index=15986, start_index=15811, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
43. AnnotationURLCitation(end_index=16483, start_index=16308, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
44. AnnotationURLCitation(end_index=16794, start_index=16619, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
45. AnnotationURLCitation(end_index=17095, start_index=16920, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
46. AnnotationURLCitation(end_index=17286, start_index=17096, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=Since%20UVRAG%20is%20a%20critical,enhancing%20CUL4A%E2%80%90mediated%20ubiquitination%20and%20degradation')
47. AnnotationURLCitation(end_index=17649, start_index=17447, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=Ubiquitination%20and%20autophagy%20regulate%20protein,blocking%20autophagy%E2%80%90dependent%20degradation%20of%20p65')
48. AnnotationURLCitation(end_index=17796, start_index=17650, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=autophagy%E2%80%90dependent%20degradation%20of%20p65%20in,HCC')
49. AnnotationURLCitation(end_index=18108, start_index=17976, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=mice,HCC%2C%20predicting%20a%20poor%20prognosis')
50. AnnotationURLCitation(end_index=18788, start_index=18658, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=the%20substrate%20tRNA%20for%20methylation,')
51. AnnotationURLCitation(end_index=19337, start_index=19147, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=match%20at%20L538%20Since%20UVRAG,enhancing%20CUL4A%E2%80%90mediated%20ubiquitination%20and%20degradation')
52. AnnotationURLCitation(end_index=19528, start_index=19338, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=Since%20UVRAG%20is%20a%20critical,enhancing%20CUL4A%E2%80%90mediated%20ubiquitination%20and%20degradation')
53. AnnotationURLCitation(end_index=19823, start_index=19633, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=Since%20UVRAG%20is%20a%20critical,enhancing%20CUL4A%E2%80%90mediated%20ubiquitination%20and%20degradation')
54. AnnotationURLCitation(end_index=21137, start_index=20994, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
55. AnnotationURLCitation(end_index=21578, start_index=21423, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=The%20human%20WDR6%20protein%20is,relevant%20effects%20of%20WDR6%20and')
56. AnnotationURLCitation(end_index=21709, start_index=21579, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=tissues,to%20reduce%20fatty%20liver%20disease')
57. AnnotationURLCitation(end_index=22085, start_index=21955, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=tissues,to%20reduce%20fatty%20liver%20disease')
58. AnnotationURLCitation(end_index=22333, start_index=22190, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
59. AnnotationURLCitation(end_index=22763, start_index=22599, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=match%20at%20L639%20PPP1CB%29%2C%20phospho,in%20the%20two%20distinct%20datasets')
60. AnnotationURLCitation(end_index=22925, start_index=22764, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=match%20at%20L649%20interacted%20with,in%20order%20to%20perform%20reciprocal')
61. AnnotationURLCitation(end_index=23203, start_index=23059, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=PPP1CB%29%2C%20phospho,in%20the%20two%20distinct%20datasets')
62. AnnotationURLCitation(end_index=23507, start_index=23358, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=phosphatase%201%20,compound%2C%20XLIX%2C%20that%20inhibits%20the')
63. AnnotationURLCitation(end_index=23651, start_index=23508, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
64. AnnotationURLCitation(end_index=23949, start_index=23819, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=tissues,to%20reduce%20fatty%20liver%20disease')
65. AnnotationURLCitation(end_index=24093, start_index=23950, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
66. AnnotationURLCitation(end_index=24389, start_index=24225, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=To%20clarify%20the%20physiological%20function,of%20mutant%20PPP1CB%20in%20which')
67. AnnotationURLCitation(end_index=24546, start_index=24390, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=Thr316%20was%20replaced%20with%20either,Thr316Ala%20and%2C%20conversely')
68. AnnotationURLCitation(end_index=24927, start_index=24763, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=To%20clarify%20the%20physiological%20function,of%20mutant%20PPP1CB%20in%20which')
69. AnnotationURLCitation(end_index=25234, start_index=25070, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=To%20clarify%20the%20physiological%20function,of%20mutant%20PPP1CB%20in%20which')
70. AnnotationURLCitation(end_index=25674, start_index=25534, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=phosphatase%201%20,the%20treatment%20of%20hepatic%20steatosis')
71. AnnotationURLCitation(end_index=25983, start_index=25834, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,the%20treatment%20of%20hepatic%20steatosis')
72. AnnotationURLCitation(end_index=26328, start_index=26159, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=protein%20kinase%20and%20upstream%20stimulatory,the%20treatment%20of%20hepatic%20steatosis')
73. AnnotationURLCitation(end_index=27049, start_index=26935, title='Wdr6 WD repeat domain 6 [Rattus norvegicus (Norway rat)] - Gene - NCBI', type='url_citation', url='https://www.ncbi.nlm.nih.gov/gene/301007#:~:text=Bibliography%20Go%20to%20the%20top,PMID')
74. AnnotationURLCitation(end_index=28068, start_index=27900, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=and%20triple%E2%80%90A%20syndrome.,immunological%20role%20for%20LUAD%C2%A0and%20LUSC')
75. AnnotationURLCitation(end_index=28542, start_index=28385, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=promotes%20its%20degradation,against%20HCC%20with%20WDR6%20dysregulation')
76. AnnotationURLCitation(end_index=28971, start_index=28808, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=The%20WD%E2%80%90repeat%20,degradation%20of%20p65%2C%20elevates%20intratumoral')
77. AnnotationURLCitation(end_index=29205, start_index=29045, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=The%20WD%E2%80%90repeat%20,chromatin%20accessibility%20at%20the%20TNF%CE%B1')
78. AnnotationURLCitation(end_index=29649, start_index=29474, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
79. AnnotationURLCitation(end_index=29939, start_index=29807, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=mice,HCC%2C%20predicting%20a%20poor%20prognosis')
80. AnnotationURLCitation(end_index=30327, start_index=30170, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=promotes%20its%20degradation,against%20HCC%20with%20WDR6%20dysregulation')
81. AnnotationURLCitation(end_index=30800, start_index=30643, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=promotes%20its%20degradation,against%20HCC%20with%20WDR6%20dysregulation')
82. AnnotationURLCitation(end_index=31145, start_index=30970, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=myeloid%E2%80%90derived%20suppressor%20cell%20,against%20HCC%20with%20WDR6%20dysregulation')
83. AnnotationURLCitation(end_index=31587, start_index=31412, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=myeloid%E2%80%90derived%20suppressor%20cell%20,against%20HCC%20with%20WDR6%20dysregulation')
84. AnnotationURLCitation(end_index=32047, start_index=31876, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=are%20reversed%20by%20TNF%CE%B1%20blockade,against%20HCC%20with%20WDR6%20dysregulation')
85. AnnotationURLCitation(end_index=32397, start_index=32226, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=are%20reversed%20by%20TNF%CE%B1%20blockade,against%20HCC%20with%20WDR6%20dysregulation')
86. AnnotationURLCitation(end_index=33384, start_index=33227, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=Our%20results%20showed%20WDR6%20was,and%20chemokines%20in%20lung%20cancer')
87. AnnotationURLCitation(end_index=33659, start_index=33502, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=Our%20results%20showed%20WDR6%20was,and%20chemokines%20in%20lung%20cancer')
88. AnnotationURLCitation(end_index=33946, start_index=33789, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=Our%20results%20showed%20WDR6%20was,and%20chemokines%20in%20lung%20cancer')
89. AnnotationURLCitation(end_index=34332, start_index=34141, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=postprogression%20survival%2C%20and%20Relapse%E2%80%90free%20survival,and%20chemokines%20in%20lung%20cancer')
90. AnnotationURLCitation(end_index=34688, start_index=34531, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=Our%20results%20showed%20WDR6%20was,and%20chemokines%20in%20lung%20cancer')
91. AnnotationURLCitation(end_index=35543, start_index=35385, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=found%20the%20expression%20of%20WDR6,and%20chemokines%20in%20lung%20cancer')
92. AnnotationURLCitation(end_index=36860, start_index=36738, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
93. AnnotationURLCitation(end_index=37131, start_index=36963, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
94. AnnotationURLCitation(end_index=37469, start_index=37294, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
95. AnnotationURLCitation(end_index=37731, start_index=37588, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
96. AnnotationURLCitation(end_index=38401, start_index=38269, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=been%20fully%20elucidated,dependent%20kinase%20%28CDK')
97. AnnotationURLCitation(end_index=39046, start_index=38899, title='WDR6 Gene - GeneCards | WDR6 Protein | WDR6 Antibody', type='url_citation', url='https://www.genecards.org/cgi-bin/carddisp.pl?gene=WDR6#:~:text=Together%20with%20methyltransferase%20FTSJ1%2C%20methylates,')
98. AnnotationURLCitation(end_index=39559, start_index=39415, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=PPP1CB%29%2C%20phospho,in%20the%20two%20distinct%20datasets')
99. AnnotationURLCitation(end_index=39670, start_index=39560, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=PPP1CB%20,These%20results')
100. AnnotationURLCitation(end_index=40205, start_index=40065, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=phosphatase%201%20,the%20treatment%20of%20hepatic%20steatosis')
101. AnnotationURLCitation(end_index=40377, start_index=40206, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=are%20reversed%20by%20TNF%CE%B1%20blockade,against%20HCC%20with%20WDR6%20dysregulation')
102. AnnotationURLCitation(end_index=41061, start_index=40903, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=found%20the%20expression%20of%20WDR6,and%20chemokines%20in%20lung%20cancer')
103. AnnotationURLCitation(end_index=41237, start_index=41062, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=myeloid%E2%80%90derived%20suppressor%20cell%20,against%20HCC%20with%20WDR6%20dysregulation')
104. AnnotationURLCitation(end_index=41789, start_index=41614, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=myeloid%E2%80%90derived%20suppressor%20cell%20,against%20HCC%20with%20WDR6%20dysregulation')
105. AnnotationURLCitation(end_index=41920, start_index=41790, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10590755/#:~:text=tissues,to%20reduce%20fatty%20liver%20disease')
106. AnnotationURLCitation(end_index=42970, start_index=42848, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
107. AnnotationURLCitation(end_index=43139, start_index=42971, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
108. AnnotationURLCitation(end_index=43297, start_index=43140, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=promotes%20its%20degradation,against%20HCC%20with%20WDR6%20dysregulation')
109. AnnotationURLCitation(end_index=43441, start_index=43298, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
110. AnnotationURLCitation(end_index=43949, start_index=43827, title='Intellectual disability‐associated gene ftsj1 is responsible for 2′‐O‐methylation of specific tRNAs - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC7403668/#:~:text=owing%2C%20in%20part%2C%20to%20the,Our')
111. AnnotationURLCitation(end_index=44245, start_index=44077, title='Association of LKB1 with a WD-repeat protein WDR6 is implicated in cell growth arrest and p27(Kip1) induction - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/17216128/#:~:text=Immunofluorescence%20staining%20revealed%20that%20WDR6,that%20WDR6%20is%20implicated%20in')
112. AnnotationURLCitation(end_index=44538, start_index=44369, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=screening%20suggesting%20a%20possible%20role,WDR6%20in%20autophagy%2C%20these%20data')
113. AnnotationURLCitation(end_index=44831, start_index=44656, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=HCC%20cells%2C%20its%20deficiency%20in,recruits%20NF%E2%80%90%CE%BAB%20to%20activate%20the')
114. AnnotationURLCitation(end_index=44989, start_index=44832, title='Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC10165360/#:~:text=promotes%20its%20degradation,against%20HCC%20with%20WDR6%20dysregulation')
115. AnnotationURLCitation(end_index=45291, start_index=45148, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=containing%20protein%206%20,for%20the%20treatment%20of%20hepatic')
116. AnnotationURLCitation(end_index=45432, start_index=45292, title='Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice | Nature Metabolism', type='url_citation', url='https://www.nature.com/articles/s42255-023-00896-7#:~:text=phosphatase%201%20,the%20treatment%20of%20hepatic%20steatosis')
117. AnnotationURLCitation(end_index=45747, start_index=45590, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=Our%20results%20showed%20WDR6%20was,and%20chemokines%20in%20lung%20cancer')
118. AnnotationURLCitation(end_index=45906, start_index=45748, title='WD repeat domain 6 as a novelty prognostic biomarker correlates with immune infiltration in lung cancer: A preliminary study - PMC', type='url_citation', url='https://pmc.ncbi.nlm.nih.gov/articles/PMC9382870/#:~:text=found%20the%20expression%20of%20WDR6,and%20chemokines%20in%20lung%20cancer')
119. AnnotationURLCitation(end_index=46256, start_index=46064, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=transduction%2C%20transcription%2C%20and%20proliferation,significant%20sequence%20similarity%20with%20Arabidopsis')
120. AnnotationURLCitation(end_index=46404, start_index=46257, title='Molecular cloning, expression analysis, and chromosome mapping of WDR6, a novel human WD-repeat gene - PubMed', type='url_citation', url='https://pubmed.ncbi.nlm.nih.gov/10903905/#:~:text=since%20its%2011%20WD%20repeats,probably%20belongs%20to%20a%20highly')