Affinage

ZC3H13

Zinc finger CCCH domain-containing protein 13 · UniProt Q5T200

Length
1668 aa
Mass
196.6 kDa
Annotated
2026-04-28
42 papers in source corpus 16 papers cited in narrative 16 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ZC3H13 is a zinc-finger CCCH-domain protein that functions as an essential structural adaptor within the nuclear m6A methyltransferase writer complex, anchoring WTAP, Virilizer/KIAA1429, and Hakai in the nucleus by bridging the mRNA-binding factor RBM15/Nito to WTAP/Fl(2)d; loss of ZC3H13 causes cytoplasmic translocation of these writer subunits and global reduction of m6A on mRNA (PMID:29547716, PMID:29535189, PMID:29555755, PMID:40959082). Through this nuclear-anchoring and bridging function, ZC3H13-dependent m6A marks are deposited on diverse target transcripts, whose fates are then determined by specific m6A readers: YTHDF2-dependent destabilization (e.g., PKM2, IQGAP1, PRDX6, KCNQ1OT1), YTHDF1-dependent translational promotion (e.g., PHF10, SNTB1), or IGF2BP1-dependent stabilization (e.g., NABP1) (PMID:35003256, PMID:36739231, PMID:40646387, PMID:35033590, PMID:40774945, PMID:39985591). These m6A-dependent regulatory activities position ZC3H13 as a modulator of stem cell self-renewal, DNA damage repair, glycolysis, ferroptosis, immune polarization, and cancer metastasis (PMID:29547716, PMID:35033590, PMID:40000487, PMID:41847860, PMID:41105668).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2018 High

    Three independent studies established that ZC3H13 (and its Drosophila orthologs Flacc/Xio) is a core component of the m6A writer complex, resolving its molecular role as a bridging adaptor that connects RBM15/Nito to WTAP/Fl(2)d and anchors the entire complex in the nucleus — loss of ZC3H13 causes WTAP, Virilizer, and Hakai to translocate to the cytoplasm and globally reduces m6A levels.

    Evidence siRNA knockdown with subcellular fractionation and IF in mESCs; reciprocal Co-IP/MS plus genetic epistasis in Drosophila and mice; colocalization and sex-determination genetics in Drosophila

    PMID:29535189 PMID:29547716 PMID:29555755

    Open questions at the time
    • No structural model of ZC3H13 or the bridging interface with RBM15 and WTAP
    • Mechanism by which ZC3H13 confers nuclear retention (NLS-dependent vs. phase separation vs. chromatin tethering) is undefined
    • Direct RNA-binding specificity of ZC3H13 zinc-finger domains uncharacterized
  2. 2018 Medium

    Beyond its writer complex role, ZC3H13 loss in colorectal cancer cells was shown to activate Ras-ERK signaling, providing early evidence that ZC3H13 regulates oncogenic pathways, though the direct m6A-target link was not identified.

    Evidence siRNA knockdown with Western blot for Ras-ERK pathway markers and proliferation/invasion assays in CRC cells

    PMID:30311220

    Open questions at the time
    • Specific m6A target transcript mediating Ras-ERK activation not identified
    • No reconstitution or epistasis with m6A reader proteins
    • Single lab without independent replication
  3. 2022 Medium

    The first specific m6A-target-reader axis was delineated: ZC3H13-dependent m6A on PHF10 mRNA promotes its YTHDF1-dependent translation, establishing that ZC3H13 controls DNA double-strand break repair via homologous recombination.

    Evidence MeRIP-qPCR, polysome profiling, HR repair reporter assay, and DNA damage foci quantification in pancreatic cancer cells

    PMID:35033590

    Open questions at the time
    • Single lab; no independent confirmation of PHF10 as a direct ZC3H13-dependent m6A target
    • Whether ZC3H13 directly binds PHF10 pre-mRNA or acts indirectly through complex recruitment is unknown
  4. 2021 Medium

    ZC3H13-mediated m6A was shown to destabilize PKM2 mRNA, linking the writer complex to glycolysis suppression and establishing that ZC3H13-dependent m6A can promote mRNA decay of metabolic transcripts.

    Evidence MeRIP-qPCR, RIP, actinomycin D chase, luciferase reporter, and gain/loss-of-function in HCC cells

    PMID:35003256

    Open questions at the time
    • The specific m6A reader mediating PKM2 destabilization was not identified
    • Single lab study in HCC cell lines
  5. 2023 Medium

    Identification of IQGAP1 mRNA as a ZC3H13-dependent m6A target destabilized via YTHDF2 in thyroid carcinoma extended the YTHDF2-dependent decay model to a second independent transcript and cancer type.

    Evidence MeRIP-qPCR, actinomycin D stability assay, YTHDF2 knockdown rescue, and xenograft model

    PMID:36739231

    Open questions at the time
    • No transcriptome-wide mapping of ZC3H13-dependent m6A sites in thyroid carcinoma
    • Single lab without independent replication
  6. 2024 Medium

    Multiple studies expanded the repertoire of ZC3H13-dependent m6A targets and reader pathways: Bax mRNA stabilization via YTHDC1 in pulmonary fibrosis and ITGA6 mRNA stabilization in COPD, demonstrating that ZC3H13 acts through different readers (YTHDC1, YTHDF2, YTHDF1, IGF2BP1) to either stabilize or destabilize transcripts depending on context.

    Evidence MeRIP, RIP, actinomycin D stability assays, reader knockdown rescue in BLM mouse model and CSE-treated lung cells

    PMID:38670474 PMID:39307407

    Open questions at the time
    • What determines which reader engages a given ZC3H13-deposited m6A site is unknown
    • Reader selectivity has not been tested in a reconstituted system
  7. 2025 Medium

    A series of studies consolidated ZC3H13's role in diverse pathological contexts — ferroptosis regulation via PRDX6/YTHDF2 and KCNQ1OT1/YTHDF2-MLL4 axes, DNA damage via NABP1/IGF2BP1, immune modulation via Spic/NF-κB, EMT via SNTB1/YTHDF1, and tumor immune microenvironment remodeling via CXCL8 — while also confirming that ZC3H13 mutation causes mislocalization of METTL3/METTL14 to the cytoplasm in human cancer.

    Evidence MeRIP, RIP, ChIP, epistasis experiments, in vivo models (CLP sepsis, AKI, TNBC xenograft, ESCC CDX, LPS liver injury, gastric cancer), pharmacological rescue

    PMID:39985591 PMID:40000487 PMID:40646387 PMID:40774945 PMID:40959082 PMID:41847860

    Open questions at the time
    • Most target identifications come from single labs and lack independent validation
    • No systematic comparison of ZC3H13-dependent versus ZC3H13-independent m6A sites genome-wide across cell types
    • Catalytic vs. scaffolding contribution of ZC3H13 zinc-finger domains remains unresolved
  8. 2026 Medium

    Transcriptome-wide m6A profiling after ZC3H13 loss in prostate cancer revealed that ZC3H13 deficiency alters both the level and target specificity of m6A, stabilizing pro-migratory transcripts and driving metastasis; FDA-approved m6A demethylase inhibitors rescued the metastatic phenotype, suggesting therapeutic tractability.

    Evidence m6A-seq, invasion/migration assays, in vivo metastasis models, patient genomic analysis, pharmacological inhibition

    PMID:41105668

    Open questions at the time
    • How ZC3H13 loss changes writer complex target specificity rather than just reducing activity is mechanistically unresolved
    • Pharmacological rescue acts on demethylase, not directly on ZC3H13 — mechanism of selectivity unclear
    • Single lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major open questions remain: the structural basis of ZC3H13's bridging function within the writer complex, the determinants governing which m6A reader engages each ZC3H13-deposited mark, whether ZC3H13 directly binds RNA substrates, and whether ZC3H13 has m6A-independent functions.
  • No high-resolution structure of ZC3H13 or its interfaces with WTAP or RBM15
  • No CLIP-based map of direct ZC3H13 RNA-binding sites
  • m6A-independent functions of ZC3H13 have not been tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-8953854 Metabolism of RNA 6 R-HSA-5357801 Programmed Cell Death 3 R-HSA-73894 DNA Repair 1
Partners
HAKAIMETTL14METTL3RBM15VIRMAWTAPYTHDF1YTHDF2
Complex memberships
m6A writer complex (METTL3-METTL14-WTAP-VIRMA-HAKAI-ZC3H13-RBM15)

Evidence

Reading pass · 16 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2018 ZC3H13 is required for nuclear localization of the ZC3H13-WTAP-Virilizer-Hakai m6A writer complex; knockdown of Zc3h13 causes WTAP, Virilizer, and Hakai to translocate to the cytoplasm, decreasing global m6A levels on mRNA and impairing mESC self-renewal. siRNA knockdown in mouse ESCs, subcellular fractionation, immunofluorescence, m6A dot-blot/quantification, differentiation assays Molecular cell High 29547716
2018 Zc3h13/Flacc promotes m6A deposition by bridging the WTAP ortholog Fl(2)d to the mRNA-binding factor Nito/Rbm15, acting as an adapter within the m6A methyltransferase complex in Drosophila and mice. Co-immunoprecipitation, mass spectrometry interactome, genetic loss-of-function (Drosophila sex determination and m6A level assays), rescue experiments Genes & development High 29535189
2018 Xio (Drosophila ortholog of ZC3H13) colocalizes and physically interacts with all known m6A writer complex subunits (METTL3, METTL14, Fl(2)d/WTAP, Vir/KIAA1429, Nito/Rbm15); loss of xio reduces m6A levels, causes Sex-lethal splicing defects, and produces sex-determination phenotypes identical to other m6A factors. Co-immunoprecipitation, immunofluorescence colocalization, genetic loss-of-function, m6A quantification, alternative splicing assays in Drosophila Proceedings of the National Academy of Sciences of the United States of America High 29555755
2018 ZC3H13 loss-of-function in colorectal cancer cells activates Ras-ERK signaling and increases expression of Snail, Cyclin D1, and Cyclin E1 while decreasing Occludin and ZO-1, identifying ZC3H13 as an upstream suppressor of the Ras-ERK pathway controlling proliferation and invasion. siRNA knockdown, Western blot for pathway components, proliferation and invasion assays Journal of cellular physiology Medium 30311220
2022 ZC3H13-mediated m6A modification of PHF10 mRNA promotes its translation in a YTHDF1-dependent manner; ZC3H13 knockdown reduces PHF10 protein, impairing homologous recombination repair of DNA double-strand breaks in pancreatic cancer cells. siRNA knockdown, MeRIP-qPCR, polysome profiling/translation assay, γH2AX/RAD51/53BP1 foci immunofluorescence, HR repair reporter assay Cancer letters Medium 35033590
2021 ZC3H13-mediated m6A modification destabilizes PKM2 mRNA, reducing glycolysis and suppressing hepatocellular carcinoma progression; this was demonstrated by mRNA stability assay, RIP, and MeRIP-qPCR showing ZC3H13-dependent m6A on PKM2 transcript. MeRIP-qPCR, RIP, mRNA stability (actinomycin D chase), luciferase reporter, gain/loss-of-function in HCC cells Journal of oncology Medium 35003256
2023 ZC3H13 promotes m6A modification of IQGAP1 mRNA, leading to its YTHDF2-dependent destabilization and degradation, thereby suppressing papillary thyroid carcinoma growth. MeRIP-qPCR, RIP, actinomycin D mRNA stability assay, YTHDF2 knockdown rescue, xenograft model Journal of the Formosan Medical Association Medium 36739231
2025 ZC3H13 mediates m6A modification of PRDX6 mRNA, facilitating its degradation in a YTHDF2-dependent manner; reduced PRDX6 permits p53 accumulation, suppresses SLC7A11, and promotes ferroptosis in alveolar macrophages during sepsis-associated acute lung injury. MeRIP-qPCR, siRNA/lentiviral knockdown in MH-S cells and CLP mouse model, YTHDF2 RIP, ferroptosis markers, epistasis (co-silencing of ZC3H13 and PRDX6) Functional & integrative genomics Medium 40646387
2025 ZC3H13-mediated m6A modification stabilizes NABP1 mRNA through an IGF2BP1-dependent reading mechanism; ZC3H13 knockdown reduces NABP1 expression, alleviating G2/M arrest and apoptosis in cisplatin-induced acute kidney injury. MeRIP-qPCR, RIP (IGF2BP1), AAV9-mediated ZC3H13 silencing in mouse AKI model, cell cycle and apoptosis flow cytometry Cellular and molecular life sciences Medium 39985591
2024 ZC3H13 enhances ITGA6 mRNA stability through m6A modification, influencing bronchial epithelial cell inflammation and fibrosis in COPD models; ZC3H13 knockdown in CSE-treated cells and smoke-exposed mice reduced inflammation, apoptosis, and EMT. MeRIP-PCR, mRNA stability (actinomycin D), siRNA knockdown in cell and mouse COPD models, ELISA, flow cytometry Cellular signalling Medium 38670474
2025 ZC3H13-mediated m6A modification reduces KCNQ1OT1 lncRNA stability in a YTHDF2-dependent manner; loss of KCNQ1OT1 prevents MLL4 recruitment to the TRABD promoter, reducing H3K4me1/2/3 and TRABD expression, thereby inducing ferroptosis and overcoming doxorubicin resistance in TNBC. RIP, RNA pulldown, ChIP, MeRIP, YTHDF2 KD rescue, xenograft model in nude mice Cell biology and toxicology Medium 40000487
2026 Loss of ZC3H13 alters m6A writer complex activity and target specificity, decreasing m6A methylation and increasing stability of pro-migratory/invasive transcripts; co-loss with RB1 and BRCA2 occurs in metastatic prostate cancer, and FDA-approved m6A demethylase inhibitors reduce metastatic capability of ZC3H13-deficient cells. Functional in vitro invasion/migration assays, in vivo metastasis models, m6A sequencing after ZC3H13 loss, patient genomic data analysis, pharmacological inhibition Cancer research Medium 41105668
2024 ZC3H13 promotes m6A modification and stabilization of Bax mRNA through the reader YTHDC1, paradoxically increasing Bax protein and promoting apoptosis in lung epithelial cells, thereby worsening pulmonary fibrosis when ZC3H13 is lost. MeRIP, RIP (ZC3H13 binding to Bax mRNA), mRNA stability assay, YTHDC1 involvement, BLM mouse model and MLE-12 cells Experimental cell research Medium 39307407
2025 ZC3H13 mediates YTHDF1-dependent m6A modification of SNTB1 mRNA, post-transcriptionally activating SNTB1 expression and promoting EMT and gastric cancer progression. MeRIP-seq, RNA-seq, Co-IP, in vitro and in vivo functional assays, YTHDF1 knockdown rescue Cell death & disease Medium 40774945
2025 ZC3H13 mutation causes abnormal nuclear-to-cytoplasmic translocation of METTL14 and METTL3 in esophageal squamous cell carcinoma, confirming conservation of the nuclear anchoring function; ZC3H13 also promotes m6A-dependent stabilization of CXCL8 mRNA, enhancing M2 macrophage infiltration via the CXCL8-CXCR2 axis. Colorimetric m6A quantification, Western blot for METTL3/METTL14 localization, CDX mouse model, ELISA, m6A stability assay Frontiers in immunology Medium 40959082
2026 Zc3h13 silencing in macrophages stabilizes Spic mRNA in an m6A-dependent manner; elevated Spic suppresses NF-κB pathway activation, shifting macrophages from pro-inflammatory to anti-inflammatory phenotype and alleviating LPS-induced liver injury. siRNA knockdown, m6A dot-blot, mRNA stability assay, NF-κB reporter, co-silencing epistasis (Spic+Zc3h13), in vivo C57BL/6 LPS model Journal of immunology Medium 41847860

Source papers

Stage 0 corpus · 42 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2018 Zc3h13 Regulates Nuclear RNA m6A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Molecular cell 754 29547716
2018 Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m6A machinery component Wtap/Fl(2)d. Genes & development 507 29535189
2018 ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. Journal of cellular physiology 110 30311220
2020 Analysis of N6-Methyladenosine Methyltransferase Reveals METTL14 and ZC3H13 as Tumor Suppressor Genes in Breast Cancer. Frontiers in oncology 98 33363011
2022 N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Military Medical Research 85 35418160
2018 Xio is a component of the Drosophila sex determination pathway and RNA N6-methyladenosine methyltransferase complex. Proceedings of the National Academy of Sciences of the United States of America 83 29555755
2022 ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer. Cancer letters 43 35033590
2012 The Trypanosoma brucei CCCH zinc finger proteins ZC3H12 and ZC3H13. Molecular and biochemical parasitology 31 22366391
2021 ZC3H13 Inhibits the Progression of Hepatocellular Carcinoma through m6A-PKM2-Mediated Glycolysis and Enhances Chemosensitivity. Journal of oncology 28 35003256
2023 Overexpressed ZC3H13 suppresses papillary thyroid carcinoma growth through m6A modification-mediated IQGAP1 degradation. Journal of the Formosan Medical Association = Taiwan yi zhi 21 36739231
2021 N6-Methyladenosine Writer Gene ZC3H13 Predicts Immune Phenotype and Therapeutic Opportunities in Kidney Renal Clear Cell Carcinoma. Frontiers in oncology 19 34497769
2023 ZC3H13 reduced DUOX1-mediated ferroptosis in laryngeal squamous cell carcinoma cells through m6A-dependent modification. Tissue & cell 16 37536262
2024 ZC3H13 promotes ITGA6 m6A modification for chronic obstructive pulmonary disease progression. Cellular signalling 15 38670474
2022 circRERE regulates the expression of GBX2 through miR-1299 and ZC3H13/N6-methyladenosine (m6A) to promote growth and invasion of hepatocellular carcinoma cells. Journal of biosciences 14 36222159
2023 ZC3H13 Enhances the Malignancy of Cervical Cancer by Regulating m6A Modification of CKAP2. Critical reviews in immunology 12 37943149
2024 Exosome-derived lncRNA A1BG-AS1 attenuates the progression of prostate cancer depending on ZC3H13-mediated m6A modification. Cell division 10 38351022
2025 Molecular mechanism of ZC3H13 -mediated ferroptosis in doxorubicin resistance of triple negative breast cancer. Cell biology and toxicology 8 40000487
2023 ZC3H13 Accelerates Keloid Formation by Mediating N6-methyladenosine Modification of HIPK2. Biochemical genetics 7 37752292
2025 Identification of m6A methyltransferase-related WTAP and ZC3H13 predicts immune infiltrates in glioblastoma. Scientific reports 6 39910141
2025 Methyltransferase ZC3H13 regulates ferroptosis of alveolar macrophages in sepsis-associated acute lung injury via PRDX6/p53/SLC7A11 axis. Functional & integrative genomics 6 40646387
2024 hsa_circ_0101050 regulated by ZC3H13 enhances tumorigenesis in papillary thyroid cancer via m6A modification. Heliyon 6 38988519
2024 ZC3H13-Mediated m6A Modification Ameliorates Acute Myocardial Infarction through Preventing Inflammation, Oxidative Stress and Ferroptosis by Targeting lncRNA93358. Inflammation 5 39107569
2024 ZC3H13 knockdown enhances the inhibitory effect of sevoflurane on gastric cancer cell malignancy by regulating the N6-methyladenosine modification of the lncRNA DLX6-AS1. Heliyon 5 39220970
2024 ZC3H13-induced the m6A modification of hsa_circ_0081723 promotes cervical cancer progression via AMPK/p53 pathway. The journal of obstetrics and gynaecology research 5 39476847
2025 The inhibition of ZC3H13 attenuates G2/M arrest and apoptosis by alleviating NABP1 m6A modification in cisplatin-induced acute kidney injury. Cellular and molecular life sciences : CMLS 4 39985591
2024 ZC3H13 promotes autophagy in bladder cancer through m6A methylation modification of PJA2 and ubiquitination of KSR1. Human cell 4 39614918
2024 m6A methyltransferase ZC3H13 improves pulmonary fibrosis in mice through regulating Bax expression. Experimental cell research 3 39307407
2022 Enterovirus 71 VP1 promotes 5-HT release by upregulating the expression of ERICH3 and methyltransferase ZC3H13. Virus research 3 35660571
2025 The role of ZC3H13 in promoting M2 macrophage infiltration via m6A methylation in esophageal squamous cell carcinoma tumor progression. Frontiers in immunology 2 40959082
2024 ZC3H13 may participate in the ferroptosis process of sepsis-induced cardiomyopathy by regulating the expression of Pnn and Rbm25. Gene 2 39284557
2025 ZC3H13 Regulates Ferroptosis to Enhance Osteogenic Differentiation in Osteoporotic BMSCs. Tissue engineering. Part A 1 40130382
2025 M6A methyltransferase ZC3H13-mediated downregulation of GPX4 mRNA stability inhibits the progression of kidney renal clear cell carcinoma (KIRC). Cellular immunology 1 40578066
2025 N(6)-methyladenosine modification of ADGRA3 by ZC3H13 suppresses papillary thyroid cancer cell malignancy by inactivating the PI3K/Akt/mTOR signaling pathway. Discover oncology 1 40890321
2026 ZC3H13 Loss Drives Cancer Metastatic Progression by Disrupting m6A RNA Methylation. Cancer research 0 41105668
2026 Silencing of Zc3h13 attenuates LPS-induced inflammatory response in macrophages via m6A-dependent stabilization of Spic mRNA. Journal of immunology (Baltimore, Md. : 1950) 0 41847860
2026 Bioinformatics and machine learning identify ITIH4 and ZC3H13 as novel mRNA biomarkers for major depressive disorder that promote microglial M1 polarization. Cytotechnology 0 41890272
2026 ZC3H13-mediated the m6A modification of PAX9 suppresses the progression of reflux esophagitis via improving esophageal epithelial barrier dysfunction. Gene 0 42044732
2025 ZC3H13 Promotes NSUN4-Mediated Chondrocyte Mitochondrial Dysfunction and Pyroptosis in Temporomandibular Joint Osteoarthritis. Cartilage 0 40433805
2025 ZC3H13 mediates N6-methyladenosine modification of SNTB1 to promote epithelial-mesenchymal transition in gastric cancer. Cell death & disease 0 40774945
2025 ZC3H13 facilitates the progression of acute myeloid leukemia through m6A-FOXP1-mediated metabolic reprogramming. Experimental hematology 0 40780498
2025 ZC3H13-induced KLRB1 upregulation relieves the injury of myocardial infarction through N [6]-methyladenosine methylation. Journal of receptor and signal transduction research 0 41175162
2025 PLAU regulated by a m6A writer ZC3H13 plays the oncogenic role in oral squamous cell carcinoma. Cytotechnology 0 41377025