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Showing ZNF106 — ZFP106 is a alias.

ZNF106

Zinc finger protein 106 · UniProt Q9H2Y7

Length
1883 aa
Mass
208.9 kDa
Annotated
2026-06-11
17 papers in source corpus 9 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZNF106 (ZFP106) is a nuclear zinc finger/WD40-domain protein required for the maintenance of motor and sensory neurons, where its loss in mice produces selective motor and sensory neuronal degeneration that is rescued by motor-neuron-specific restoration of the protein (PMID:28072389, PMID:26604141). Mechanistically, ZNF106 is an RNA-binding protein that specifically binds GGGGCC repeat RNA and associates with the ALS-linked RNA-binding proteins TDP-43 and FUS (PMID:28072389). It binds the G-quadruplex structures formed by these repeats and induces a conformational change, thereby inhibiting RNA foci formation and suppressing RAN translation of dipeptide repeat proteins in patient-derived C9orf72 cells, and it suppresses GGGGCC-induced neurotoxicity in a Drosophila model (PMID:28072389, PMID:39042693). ZNF106 functions in nuclear RNA processing compartments: it associates with the splicing factor RBM39 at nuclear speckles and relocalizes to the nucleolus when pre-mRNA synthesis is blocked (PMID:27418600), and its disruption causes aberrant splicing of the Nogo/Rtn4 locus with ectopic NOGO-A expression that destabilizes neuromuscular junctions (PMID:27418600). The gene was originally identified as the mouse H3 minor histocompatibility locus and is transcribed from a dual promoter system, a ubiquitous NRF-1-regulated promoter and a muscle-specific myogenin-activated promoter (PMID:15656981, PMID:9846490).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 1998 High

    Established the molecular identity of the gene by positional cloning, defining its domain architecture and an unexpected role as the mouse H3 minor histocompatibility antigen.

    Evidence Positional cloning with CTL-based selection, peptide binding assays, and domain analysis

    PMID:9846490

    Open questions at the time
    • Did not address the protein's biochemical or RNA-related function
    • Functional role of the zinc finger and WD40 domains undefined
  2. 2004 High

    Resolved how ZNF106 expression is controlled, showing distinct ubiquitous and muscle-specific transcriptional programs.

    Evidence 5'-RACE, promoter deletion, NRF-1 site mutagenesis, dominant-negative NRF-1, and myogenin binding assays

    PMID:15656981

    Open questions at the time
    • Does not link transcriptional control to protein function
    • Physiological consequence of muscle-specific isoform unknown
  3. 2005 Medium

    Mapped domain-specific subnuclear targeting, attributing nucleolar localization to the WD40 region and nucleoplasmic body recruitment to an N-terminal region.

    Evidence Deletion analysis, yeast two-hybrid, and co-localization for TSG118 and TSPYL interactions

    PMID:15833274

    Open questions at the time
    • TSPYL interaction supported only by yeast two-hybrid and co-localization (Low confidence)
    • No biochemical reconstitution of either interaction
    • Functional significance of nucleolar targeting unresolved
  4. 2015 Medium

    Demonstrated a cell-intrinsic requirement for ZNF106 in neuronal survival and uncovered a mitochondrial bioenergetic deficit accompanying degeneration.

    Evidence Zfp106 knockout mouse characterization and Complex I activity assay in embryonic motor neurons

    PMID:26604141

    Open questions at the time
    • Whether the Complex I defect is causal or secondary is unresolved
    • Single method for the mitochondrial phenotype
    • Molecular link between ZNF106 and Complex I not defined
  5. 2015 Medium

    Placed ZNF106 at the rDNA promoter as a factor targeting RNA Pol I, implicating it in ribosomal RNA transcription.

    Evidence ePICh chromatin enrichment proteomics at the ribosomal RNA gene promoter

    PMID:25812914

    Open questions at the time
    • Limited functional follow-up on Pol I regulation
    • Mechanism of Pol I recruitment unknown
    • Single lab, single method
  6. 2016 Medium

    Connected ZNF106 to pre-mRNA splicing machinery and identified a downstream splicing defect explaining neuromuscular junction destabilization.

    Evidence Co-IP with RBM39, immunofluorescence/fractionation, transcription-inhibition relocalization, and Nogo/Rtn4 splicing analysis in knockout muscle

    PMID:27418600

    Open questions at the time
    • Direct role of ZNF106 in the splicing reaction not biochemically reconstituted
    • Single lab
    • Generality of splicing targets beyond Rtn4 unknown
  7. 2017 High

    Linked ZNF106 to C9orf72 ALS biology by identifying GGGGCC RNA binding, interactions with TDP-43 and FUS, and suppression of repeat toxicity in vivo.

    Evidence AP-MS, RNA binding assays, knockout/rescue in mice, and Drosophila repeat-toxicity suppression

    PMID:26604141 PMID:28072389

    Open questions at the time
    • Mechanism by which RNA binding suppresses toxicity not fully resolved at this stage
    • Direct versus indirect interaction with TDP-43/FUS not dissected
  8. 2017 Medium

    Characterized ZNF106 as a substrate of CBP acetylation through a disorder-preserving interaction between intrinsically disordered regions.

    Evidence Yeast two-hybrid, NMR spectroscopy, cross-linking, and competition-binding assays

    PMID:28680062

    Open questions at the time
    • Acetylation itself not directly demonstrated beyond substrate identification
    • Functional consequence of acetylation unknown
    • Single lab
  9. 2024 High

    Defined the biochemical mechanism of repeat-toxicity suppression: ZNF106 binds and conformationally remodels GGGGCC RNA G-quadruplexes to reduce foci and RAN translation.

    Evidence G-quadruplex binding and conformational assays, RNA foci quantification, RAN translation reporters, and C9orf72 patient-derived cells

    PMID:39042693

    Open questions at the time
    • In vivo therapeutic efficacy not established
    • Structural basis of the conformational change not solved
    • Whether endogenous ZNF106 levels are sufficient for protection in patients unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ZNF106's roles in rRNA transcription, pre-mRNA splicing, mitochondrial function, and G-quadruplex remodeling integrate into a single mechanism of neuronal maintenance remains unresolved.
  • No unified model connecting nucleolar, splicing, and RNA-repeat activities
  • No structure of ZNF106 or its RNA-bound complexes
  • Causal hierarchy between splicing defects, mitochondrial deficit, and neurodegeneration undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 2
Pathway
R-HSA-1643685 Disease 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CREBBPFUSNRF1RBM39TARDBPTSPYL

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 Zfp106 specifically binds GGGGCC RNA repeats and interacts with multiple RNA-binding proteins including the ALS-associated factors TDP-43 and FUS, as identified by affinity purification-mass spectrometry. Affinity purification-mass spectrometry (AP-MS), RNA binding assay eLife High 28072389
2017 Zfp106 knockout mice develop severe motor neuron degeneration, which is rescued by transgenic restoration of Zfp106 specifically in motor neurons, establishing a cell-autonomous requirement of Zfp106 in motor neuron survival. Transgenic mouse rescue experiment (motor neuron-specific restoration), knockout mouse phenotype eLife High 26604141 28072389
2017 Zfp106 potently suppresses GGGGCC repeat-induced neurotoxicity in a Drosophila model of C9orf72 ALS. Drosophila genetic model of C9orf72 ALS with Zfp106 overexpression eLife Medium 28072389
2016 ZFP106 associates with the core splicing factor RBM39 and localizes to nuclear speckles adjacent to spliceosomes; upon inhibition of pre-mRNA synthesis, ZFP106 translocates with other splicing factors to the nucleolus. Co-immunoprecipitation, immunofluorescence/subcellular fractionation, live-cell imaging upon transcription inhibition Proceedings of the National Academy of Sciences of the United States of America Medium 27418600
2016 Genetic disruption of Zfp106 in mice results in altered splicing of the Nogo (Rtn4) gene locus in skeletal muscle, causing ectopic expression of NOGO-A, an inhibitor of nerve regeneration that destabilizes neuromuscular junctions. Zfp106 knockout mouse, RNA splicing analysis, protein expression analysis Proceedings of the National Academy of Sciences of the United States of America Medium 27418600
2015 Zfp106-deficient mice display selective motor and sensory neuronal degeneration in spinal cord and peripheral nervous system, with embryonic Zfp106−/− motor neurons showing inhibition of mitochondrial Complex I within the electron transport chain. Zfp106 knockout mouse characterization, mitochondrial Complex I activity assay in embryonic motor neurons Human molecular genetics Medium 26604141
2015 ZFP106 is identified as a novel factor that regulates transcription initiation by RNA Polymerase I at the ribosomal RNA gene promoter, targeting RNA Pol I to the promoter. ePICh (end-targeting proteomics of isolated chromatin segments), chromatin affinity capture Nature communications Medium 25812914
2005 The C-terminal WD40 repeat region of ZFP106 is required for nucleolar targeting; this domain interacts with TSG118, which co-localizes with ZFP106 in the nucleolus, and TSG118 downregulation during terminal differentiation coincides with loss of nucleolar ZFP106. Deletion analysis, yeast two-hybrid, co-localization by immunofluorescence, co-expression studies The international journal of biochemistry & cell biology Medium 15833274
2005 The N-terminal region (amino acids 412–781) of ZFP106 interacts with TSPYL (a nucleosome assembly protein family member) and is recruited to TSPYL-positive nucleoplasmic bodies; this recruitment requires a TSPYL domain absent in the mutant protein associated with sudden infant death syndrome. Yeast two-hybrid, domain deletion analysis, co-localization The international journal of biochemistry & cell biology Low 15833274
2004 ZFP106 gene expression is driven by two distinct promoters: a ubiquitous TATA-less CpG island promoter (P1) regulated by NRF-1, and a muscle-specific TATA box-containing promoter (P2) activated by myogenin binding to three critical E-boxes; SH3BP3 (previously described as a separate gene) corresponds to a rare alternatively spliced P2 transcript. 5'-RACE, promoter deletion analysis, mutagenesis of NRF-1 binding site, dominant-negative NRF-1 transfection, in situ hybridization, myogenin binding assay Gene High 15656981
1998 The H3a (Zfp106) gene encodes a 1888-amino acid protein with three zinc fingers and a beta-transducin (WD40) domain; allelic variants encode an H2-Db-binding nonamer peptide that mediates cytotoxic T cell responses, establishing ZFP106 as the gene underlying the mouse H3 minor histocompatibility complex. Positional cloning, CTL-based selection, peptide binding assays, protein domain analysis Immunity High 9846490
2017 ZFP106 is identified as a novel substrate for CBP-mediated acetylation; the disordered linker region ID3 of CBP transiently interacts with an intrinsically disordered region (IDR) of ZFP106, maintaining disorder in both regions. Yeast two-hybrid screening, NMR spectroscopy, cross-linking experiments, competition-binding assays Scientific reports Medium 28680062
2024 Zfp106 binds RNA G-quadruplexes and causes a conformational change in the G-quadruplex structure formed by GGGGCC repeats; Zfp106 inhibits formation of RNA foci and significantly reduces RAN translation (including DPR protein levels) caused by GGGGCC repeats in cultured mammalian cells and C9orf72 patient-derived cells. RNA G-quadruplex binding assay, conformational change assay, RNA foci quantification, RAN translation reporter assay, patient-derived cell studies Proceedings of the National Academy of Sciences of the United States of America High 39042693

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Suppression of C9orf72 RNA repeat-induced neurotoxicity by the ALS-associated RNA-binding protein Zfp106. eLife 39 28072389
2017 Linking functions: an additional role for an intrinsically disordered linker domain in the transcriptional coactivator CBP. Scientific reports 37 28680062
2016 Severe muscle wasting and denervation in mice lacking the RNA-binding protein ZFP106. Proceedings of the National Academy of Sciences of the United States of America 35 27418600
1998 Positional cloning and molecular characterization of an immunodominant cytotoxic determinant of the mouse H3 minor histocompatibility complex. Immunity 33 9846490
2015 End-targeting proteomics of isolated chromatin segments of a mammalian ribosomal RNA gene promoter. Nature communications 32 25812914
2020 Genome-wide association study for growth and fatness traits in Chinese Sujiang pigs. Animal genetics 27 31909836
2005 Subcellular recruitment by TSG118 and TSPYL implicates a role for zinc finger protein 106 in a novel developmental pathway. The international journal of biochemistry & cell biology 27 15833274
2017 Genetic risk variants for metabolic traits in Arab populations. Scientific reports 24 28106113
2015 Deficiency of the zinc finger protein ZFP106 causes motor and sensory neurodegeneration. Human molecular genetics 17 26604141
2023 Genome-wide association study for the primary feather color trait in a native Chinese duck. Frontiers in genetics 15 36936414
2017 Genome-wide analysis of DNA methylation and their associations with long noncoding RNA/mRNA expression in non-small-cell lung cancer. Epigenomics 14 28111977
2004 Dual promoter structure of ZFP106: regulation by myogenin and nuclear respiratory factor-1. Gene 11 15656981
2024 Zfp106 binds to G-quadruplex RNAs and inhibits RAN translation and formation of RNA foci caused by G4C2 repeats. Proceedings of the National Academy of Sciences of the United States of America 10 39042693
2022 Modification of alternative splicing in bovine somatic cell nuclear transfer embryos using engineered CRISPR-Cas13d. Science China. Life sciences 9 35524909
2016 Genome-Wide Analysis in Swine Associates Corneal Graft Rejection with Donor-Recipient Mismatches in Three Novel Histocompatibility Regions and One Locus Homologous to the Mouse H-3 Locus. PloS one 9 27010211
2021 Whole-exome Sequencing Identifies SLC52A1 and ZNF106 Variants as Novel Genetic Risk Factors for (Early) Multiple-organ Failure in Acute Pancreatitis. Annals of surgery 7 33427755
2025 Identification of Novel Genetic Variants and Food Intake Factors Associated with Type 2 Diabetes in South Korean Adults, Using an Illness-Death Model. International journal of molecular sciences 3 40141237

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