Affinage

PCIF1

mRNA (2'-O-methyladenosine-N(6)-)-methyltransferase · UniProt Q9H4Z3

Length
704 aa
Mass
80.7 kDa
Annotated
2026-06-10
37 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PCIF1 is a nuclear cap-specific RNA methyltransferase that co-transcriptionally deposits N6,2'-O-dimethyladenosine (m6Am) on the first transcribed nucleotide of capped mRNAs, thereby tuning transcript stability and translation across diverse cellular programs (PMID:32814042, PMID:33982754). Its WW domain directly and preferentially binds the Ser5-phosphorylated (hyperphosphorylated) CTD of RNA polymerase II, recruiting the enzyme to transcription start sites of active genes in a manner strictly dependent on transcriptional activity and CTD phosphorylation, which positions it for cotranscriptional methylation of nascent mRNA caps (PMID:12565871, PMID:33982754). Biochemically PCIF1 most efficiently methylates a 2'-O-methylated, capped 5' adenosine, with progressively lower activity on uncapped 5'-Am, internal adenosines, and DNA or hybrid substrates (PMID:35189146, PMID:35605980). Through m6Am marking of specific targets PCIF1 either stabilizes transcripts (FOS, ACE2/TMPRSS2, LPP3, Wnt11/Fzd4/Fgfr2) or suppresses their translation/stability (TM9SF1, BICD2, MTF2, Maf1, Gap43), thereby controlling cancer cell invasion and proliferation, viral infection, ciliogenesis, osteogenic differentiation of mesenchymal stem cells, neuropathic pain, and CD8+ T cell ferroptosis resistance and antitumor activity (PMID:36514940, PMID:35597784, PMID:36689652, PMID:38526325, PMID:39422663, PMID:39762445, PMID:40764612, PMID:41712381, PMID:41941537). Target selection is shaped by interchangeable cofactors: CTBP2 and SERBP1 each form complexes with PCIF1 to direct m6Am deposition onto context-specific substrates such as TET2 and Maf1 mRNA (PMID:37643007, PMID:40764612). PCIF1 also executes methyltransferase-independent activities, suppressing type I interferon induction by attenuating IRF3 phosphorylation and nuclear translocation, and acting through its WW domain to restrain glioma cell proliferation (PMID:41677666, PMID:41131141). In addition to its earliest-characterized role as SPOP/PCIF1 targeting the transcription factor PDX-1 for ubiquitination and proteasomal degradation to modulate β-cell survival, a cytoplasmic pool of PCIF1 redistributes to stress granules and modulates their dynamics (PMID:20811152, PMID:38766247).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 2003 High

    Established the molecular handle by which PCIF1 engages the transcription machinery, showing its WW domain selectively reads the phosphorylated Pol II CTD.

    Evidence CTD probe library screening, in vitro binding, Co-IP and immunofluorescence in HeLa cells

    PMID:12565871

    Open questions at the time
    • Did not define an enzymatic activity for PCIF1
    • Functional consequence of CTD binding unknown at this stage
  2. 2004 High

    Identified PCIF1 (SPOP) as a nuclear inhibitor of the β-cell transcription factor PDX-1, the first specific functional partner.

    Evidence Yeast two-hybrid, Co-IP, reporter assays and immunofluorescence in MIN6 cells

    PMID:15121856

    Open questions at the time
    • Mechanism of inhibition not resolved
    • Did not connect PDX-1 regulation to any catalytic or RNA-related activity
  3. 2006 High

    Mapped the TRAF and POZ domains as the PDX-1 interaction module and linked a diabetes-associated PDX-1 mutation to loss of PCIF1 regulation, establishing physiological relevance.

    Evidence Endogenous Co-IP, domain deletion/mutagenesis and reporter assays in MIN6 cells

    PMID:17126328

    Open questions at the time
    • Inhibitory mechanism shown distinct from classical POZ corepressor recruitment but not otherwise defined
  4. 2009 Medium

    Showed PCIF1 negatively modulates Pol II transcriptional activity in vivo and relates to Pin1 in CTD regulation, reinforcing a transcription-linked function.

    Evidence PCIF1-knockout DT40 cells, reconstitution and transcriptional reporter assays

    PMID:19682092

    Open questions at the time
    • Mechanism of transcriptional repression unresolved
    • Single lab; no biochemical activity assigned
  5. 2010 High

    Demonstrated PCIF1 targets PDX-1 for ubiquitination and proteasomal degradation in vivo, defining a concrete biological output controlling β-cell mass and glucose homeostasis.

    Evidence siRNA knockdown, heterozygous mouse genetics, ubiquitination and protein stability assays, glucose tolerance tests

    PMID:20811152

    Open questions at the time
    • Relationship of this E3-adaptor-like activity to PCIF1's later-defined methyltransferase function unresolved
  6. 2020 High

    Defined PCIF1 as the mammalian cap-specific m6Am methyltransferase, reframing it as an RNA-modifying enzyme and linking m6Am to transcript stability.

    Evidence Pcif1 knockout mice, transcriptome analysis, in vitro methyltransferase assays, cross-species functional comparison

    PMID:30679132 PMID:32814042

    Open questions at the time
    • How m6Am mechanistically alters individual transcript fate not yet resolved
    • Catalytic-dead Drosophila ortholog implies methylation-independent roles not yet explored
  7. 2021 High

    Localized PCIF1-dependent methylation to nascent mRNA by showing recruitment to active transcription start sites entirely dependent on Ser5-CTD phosphorylation, unifying the CTD-binding and methyltransferase activities into a cotranscriptional model.

    Evidence ChIP, subcellular fractionation, immunofluorescence and transcription-inhibition experiments in HeLa cells

    PMID:33982754

    Open questions at the time
    • Did not address determinants of substrate-specific methylation outcomes
  8. 2021 High

    Connected PCIF1 m6Am activity to antiviral and immune outcomes, showing it modifies viral mRNA caps to dampen IFN-β responses and restricts HIV via ETS1 stabilization, with Vpr-driven PCIF1 degradation as a viral counter-strategy.

    Evidence Cell-based antiviral assays, in vitro methyltransferase assays, PCIF1 KO and catalytic mutants, m6Am-seq, Co-IP

    PMID:34266951 PMID:34545078

    Open questions at the time
    • Opposing pro- and anti-viral roles across viruses not mechanistically reconciled
    • Selectivity of viral vs host cap modification undefined
  9. 2022 High

    Quantified PCIF1's substrate hierarchy, establishing cap-Am as the preferred substrate while documenting measurable activity on uncapped RNA, internal adenosines, and DNA/hybrid substrates.

    Evidence In vitro kinetic and methyltransfer assays with defined RNA, DNA and hybrid substrates

    PMID:35189146 PMID:35605980

    Open questions at the time
    • Physiological relevance of ancillary internal-A and DNA methylation activities unestablished
  10. 2022 High

    Showed PCIF1 m6Am drives cancer cell aggressiveness through specific mRNA targets, stabilizing FOS in colorectal cancer and suppressing TM9SF1 translation in gastric cancer.

    Evidence CRISPR/Cas9 KO, m6Am-seq, mRNA stability and translation assays, xenograft and immunocompetent tumor models, anti-PD-1 treatment

    PMID:35597784 PMID:36514940

    Open questions at the time
    • Why some m6Am targets are stabilized and others translationally repressed not explained
    • Determinants of target selection across tissues unknown
  11. 2023 High

    Identified CTBP2 as the first PCIF1 cofactor directing m6Am deposition and promoter SARS-CoV-2 entry-factor mRNA stabilization, advancing both the cofactor concept and infection biology.

    Evidence Co-IP, CLIP-Seq, m6Am-seq, KO and translation assays; m6Am-exo-seq and catalytic-mutant rescue in lung epithelial cells

    PMID:36689652 PMID:37643007

    Open questions at the time
    • How cofactors reprogram substrate specificity mechanistically unresolved
    • Whether additional cofactors exist not yet known at this stage
  12. 2024 High

    Expanded the m6Am target landscape into ciliogenesis, renal cancer metabolism, macrophage immunity, and bidirectional transcript regulation, demonstrating broad context-specific control.

    Evidence PCIF1 depletion with proteomics, m6Am-seq/exo-seq, LC-MS site mapping, mRNA stability/translation assays, conditional KO mice, MeRIP-qPCR

    PMID:38526325 PMID:39290151 PMID:39422663 PMID:39451207

    Open questions at the time
    • Mechanistic basis for opposite-direction regulation of RAB23 vs CNOT6 unexplained
    • Whether m6A vs m6Am marks are distinguished in some targets unclear
  13. 2024 Medium

    Revealed a cytoplasmic, non-cotranscriptional pool of PCIF1 that localizes to stress granules and binds mRNA coding sequences, broadening its functional repertoire beyond cap methylation.

    Evidence Fractionation, immunofluorescence, Co-IP with G3BP, eCLIP, ChIP-Seq, overexpression and KO (preprint)

    PMID:38766247

    Open questions at the time
    • Preprint; awaits peer review
    • Catalytic dependence of stress granule role undefined
    • Functional consequence of CDS binding unknown
  14. 2025 High

    Established PCIF1 as a negative regulator of CD8+ T cell antitumor responses and identified SERBP1 as a second cofactor, linking m6Am control to immunotherapy efficacy and neural signaling.

    Evidence Conditional KO mice, scRNA-seq, proteomics, m6Am-seq, ferroptosis and CAR-T assays; Co-IP, AAV manipulation and behavioral assays

    PMID:39762445 PMID:40764612

    Open questions at the time
    • How distinct cofactors are selected in different cell types unknown
    • Whether SERBP1 and CTBP2 complexes are mutually exclusive unresolved
  15. 2025 Medium

    Defined methyltransferase-independent PCIF1 functions, showing the WW domain restrains glioma proliferation and modulates PCIF1 stability/localization independent of catalysis.

    Evidence Domain mutagenesis, isolated WW domain expression, Co-IP with Pol II, proteasome/autophagy inhibitor assays, tumor models

    PMID:41131141

    Open questions at the time
    • Single lab
    • Mechanism by which WW domain controls PCIF1 degradation incompletely defined
  16. 2026 High

    Consolidated PCIF1's role across interferon signaling, neural plasticity, osteogenesis and cancer, including a methyltransferase-independent suppression of IRF3/type I IFN and upstream transcriptional control of PCIF1 by GLI2.

    Evidence PCIF1 KO with poly(I:C), IRF3 assays and catalytic-mutant rescue; conditional KO mice, m6Am-seq, ChIP, electrophysiology, MSC-specific KO with WNT agonist rescue; phosphoinositide and AKT analyses

    PMID:41677666 PMID:41712381 PMID:41941537 PMID:42145053

    Open questions at the time
    • How catalytic vs non-catalytic functions are partitioned in vivo unresolved
    • Integration of transcriptional (GLI2) and post-transcriptional (m6Am) layers incompletely mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PCIF1 reconciles its multiple molecular activities — cap m6Am methyltransferase, methyltransferase-independent IRF3/IFN suppressor, WW-domain growth regulator, and the early SPOP/PDX-1 ubiquitination-adaptor role — within a single coherent regulatory logic remains unresolved.
  • No structural model integrating cofactor binding with substrate selection
  • Relationship between the SPOP/ubiquitination function and RNA methyltransferase function unexplained
  • Rules governing transcript stabilization vs destabilization by m6Am undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0016740 transferase activity 3 GO:0140110 transcription regulator activity 3 GO:0003723 RNA binding 2
Localization
GO:0005634 nucleus 4 GO:0000228 nuclear chromosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 5 R-HSA-8953854 Metabolism of RNA 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
CTBP2G3BPPDX-1RNA POL II (POLR2A CTD)SERBP1VPR (HIV)
Complex memberships
PCIF1-CTBP2 complexPCIF1-SERBP1 complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2003 PCIF1 contains a WW domain that directly and preferentially binds to the phosphorylated (hyperphosphorylated) CTD of RNA polymerase II (RNAP IIO) compared to unphosphorylated CTD, both in vitro and in vivo. PCIF1 and endogenous RNAP IIO co-localize in the cell nucleus. 32P-labeled CTD probe screening of cDNA library, in vitro binding assay, co-immunoprecipitation, double immunofluorescence in HeLa cells Biochemical and biophysical research communications High 12565871
2004 PCIF1 (also called SPOP) interacts with the C-terminus of PDX-1 both in vitro and in vivo, localizes to the nucleus in a speckled pattern, and inhibits PDX-1 transactivation of target gene promoters in a dose-dependent manner requiring critical amino acids in the PDX-1 C-terminus. Co-immunoprecipitation, yeast two-hybrid, reporter gene assays, immunofluorescence, overexpression in MIN6 cells Molecular and cellular biology High 15121856
2006 Within PCIF1, both the TRAF and POZ domains are required for physical and functional interaction with the C-terminus of PDX-1; the C-terminal domain of PCIF1 directs its nuclear localization. The human PDX-1 diabetes-associated mutation E224K disrupts PCIF1-mediated inhibition of PDX-1 transactivation. Inhibition occurs by a mechanism distinct from classical POZ domain recruitment of co-repressors/HDACs. Co-immunoprecipitation of endogenous proteins in MIN6 cells, domain deletion/mutation analysis, reporter gene assays FEBS letters High 17126328
2009 PCIF1 negatively modulates RNA Pol II activity in vivo. In PCIF1-deficient chicken DT40 cells, Pin1 (a prolyl isomerase with overlapping CTD-binding specificity) is significantly upregulated. PCIF1 and Pin1 share overlapping subcellular localization and similar inhibitory effects on transcriptional activation by Pol II. PCIF1-knockout DT40 cell lines, reconstitution experiments, transcriptional reporter assays, subcellular localization studies Genes to cells Medium 19682092
2010 PCIF1 (SPOP) targets PDX-1 for ubiquitination and proteasomal degradation. Silencing of Pcif1 increases Pdx1 protein levels in cultured mouse β cells. Pcif1 heterozygosity normalizes Pdx1 protein levels in Pdx1+/- islets, improves glucose homeostasis, β cell function, and normalizes β cell mass by modulating β cell survival. siRNA knockdown, heterozygous mouse genetics, protein stability assays, ubiquitination assays, glucose tolerance tests, β cell mass measurements The Journal of clinical investigation High 20811152
2019 PCIF1 (also called CAPAM) is a mRNA cap adenosine N6-methyltransferase that methylates adenosine when it is the first transcribed nucleotide of capped mRNAs. Review/summary citing identification of enzymatic activity (references original biochemical characterization studies) Trends in biochemical sciences Medium 30679132
2020 PCIF1 is the mammalian cap-specific m6Am RNA methyltransferase responsible for N6-methylation of 2'-O-methyladenosine at the first transcribed position. Loss of PCIF1 in mice does not affect viability or fertility but reduces body weight. Transcriptome analyses support a role for cap-specific m6Am in stabilizing transcripts. Drosophila Pcif1 is catalytically dead but retains Ser5-phosphorylated CTD binding. Trypanosoma Pcif1 is an m6Am methylase contributing to hypermethylated cap4. Pcif1 knockout mice, transcriptome analysis, biochemical methyltransferase assay, phylogenetic/functional comparison across species Cell reports High 32814042
2021 PCIF1 efficiently modifies VSV mRNA cap structures to m7Gpppm6Am and attenuates the antiviral effects of interferon-β. PCIF1-dependent modification of VSV mRNA caps does not affect mRNA stability, translation, or viral infectivity, but specifically reduces the antiviral response. Cells lacking PCIF1 or expressing catalytically inactive PCIF1 show augmented inhibition of viral replication after IFN-β treatment. PCIF1 also modifies mRNA caps of rabies and measles viruses. Cell-based antiviral assays, in vitro biochemical methyltransferase assays, PCIF1 knockout cells, catalytically inactive PCIF1 mutant, mRNA stability/translation assays Proceedings of the National Academy of Sciences of the United States of America High 34266951
2021 PCIF1 is recruited to promoters of a broad range of Pol II-transcribed genes, predominantly at transcription start sites, in a manner entirely dependent on transcriptional activity and Ser5-phosphorylation of the CTD. PCIF1 is mainly localized to transcriptionally active chromatin, suggesting cotranscriptional N6-methylation of the first adenosine of nascent mRNAs. Subcellular fractionation, immunofluorescence microscopy, chromatin immunoprecipitation (ChIP) in HeLa cells, transcription inhibition experiments Journal of biochemistry High 33982754
2021 HIV Vpr protein interacts with PCIF1 and induces PCIF1 ubiquitination and degradation, thereby reprogramming the host m6Am RNA methylome. PCIF1 methyltransferase activity restricts HIV replication. PCIF1 inhibits HIV infection by enhancing stability of the transcription factor ETS1, which binds the HIV promoter to regulate viral transcription. Co-immunoprecipitation, PCIF1-depleted T cells, m6Am-seq, ubiquitination assay, viral replication assays, ETS1 stability analysis Nature communications High 34545078
2022 PCIF1 preferentially binds 2'-O-methylated Am over unmodified A due to increased binding affinity (KM ~0.4 μM for uncapped 5'-Am vs ~0.3 μM for cap analog). PCIF1 can methylate uncapped 5'-Am oligonucleotides with only ~5-6 fold lower activity than capped substrates. PCIF1 has ancillary methylation activity on internal adenosines (A and Am) with much lower efficiency. PCIF1 activity order: cap-Am > uncapped 5'-Am >> internal A/Am. In vitro binding and methyltransfer assays with defined substrates, kinetic analysis (KM measurements) The Journal of biological chemistry High 35189146
2022 PCIF1 has significant methylation activity on single-stranded DNA deoxyadenosine, double-stranded RNA/DNA hybrids, and double-stranded DNA, though with lower catalytic efficiency than on its preferred RNA substrate. Activity order: ssRNA > RNA/DNA hybrid > ssDNA > dsDNA. In vitro enzymatic characterization with defined DNA and hybrid substrates Biochemistry High 35605980
2022 CRISPR/Cas9-mediated depletion of PCIF1 in human colorectal cancer (CRC) cells leads to loss of cell migration, invasion, and colony formation. PCIF1 stabilizes FOS mRNA via m6Am modification; FOS in turn drives TGF-β regulation and tumor growth. During anti-PD-1 immunotherapy, the PCIF1-STAT1/IFITM3-IFN-γ axis also contributes to resistance. CRISPR/Cas9 KO, xenograft mouse models, m6Am-seq, mRNA stability assays, immunocompetent mouse tumor models, anti-PD-1 treatment The EMBO journal High 36514940
2022 PCIF1 is the m6Am methyltransferase responsible for m6Am modification in gastric cancer; PCIF1 modifies TM9SF1 mRNA with m6Am leading to decreased TM9SF1 translation. TM9SF1 reverses the effects of PCIF1 on gastric cancer cell aggressiveness. m6Am-seq analysis, PCIF1 silencing, translation assays, mouse tumor models, rescue experiments with TM9SF1 Cell discovery High 35597784
2023 PCIF1 promotes SARS-CoV-2 infection by sustaining expression of coronavirus receptors ACE2 and TMPRSS2 via m6Am-dependent mRNA stabilization. In PCIF1-depleted cells, ACE2/TMPRSS2 expression and viral infection are rescued by wild-type but not catalytically inactive PCIF1. CRISPR/Cas9 genome editing, genome-wide m6Am-exo-seq, RNA-seq, catalytically inactive PCIF1 rescue, viral infection assays in primary lung epithelial cells Proceedings of the National Academy of Sciences of the United States of America High 36689652
2023 CTBP2 is a cofactor of PCIF1 that promotes m6Am deposition on mRNA. CTBP2 binds similar mRNAs as PCIF1 (CLIP-Seq). Knockout of CTBP2 reduces PCIF1 occupancy on TET2 mRNA; the PCIF1-CTBP2 complex negatively regulates TET2 mRNA translation. Co-immunoprecipitation identifying CTBP2 as PCIF1 cofactor, CLIP-Seq, m6Am-Seq at single-base resolution, CTBP2/PCIF1 KO, translation assays The Journal of clinical investigation High 37643007
2024 PCIF1 acts as a negative regulator of ciliogenesis through its m6Am methyltransferase activity. PCIF1 regulates BICD2 protein levels by reducing the stability and translation efficiency of BICD2 mRNA via m6Am modification. Depletion of PCIF1 increases BICD2 levels and promotes ciliation; BICD2 knockdown reverses the ciliation phenotype of PCIF1-depleted cells. PCIF1 depletion in RPE-1 cells, quantitative proteomics, m6Am-seq, single-base resolution LC-MS of m6Am site, mRNA stability and translation assays, epistasis rescue experiments The Journal of cell biology High 38526325
2024 PCIF1 promotes renal cell carcinoma progression by enhancing translation of LPP3 mRNA via m6Am modification. LPP3 regulates phosphatidic acid metabolism, preventing its mitochondrial accumulation and facilitating mitochondrial fission. Depletion of PCIF1 sensitizes RCC to sunitinib. m6Am-Exo-Seq identifying LPP3 as target, translation assays, mitochondrial morphology analysis, in vivo tumor models, pharmacological sensitivity assays Advanced science High 39422663
2024 PCIF1 loss attenuates periodontal inflammation. PCIF1 promotes macrophage phagocytosis and migration through m6Am modification of Csf1r (CSF1R) mRNA signaling. Whole-body and myeloid lineage-specific Pcif1 knockout mice, macrophage phagocytosis and migration assays, m6Am analysis of Csf1r Journal of dental research Medium 39290151
2024 PCIF1 regulates the stability of RAB23 and CNOT6 mRNAs in opposite directions through m6A/m6Am modification. PCIF1 suppression reduces m6A levels of RAB23 and CNOT6 mRNAs. Rescue experiments confirm that PCIF1's methyltransferase activity is required for these regulatory effects. siRNA knockdown, mRNA stability assays, MeRIP-qPCR, rescue with wild-type vs catalytically inactive PCIF1 Cells Medium 39451207
2024 A population of PCIF1 is localized to the cytoplasm (not exclusively nuclear). Upon oxidative stress, PCIF1 redistributes to stress granules and physically interacts with G3BP and other stress granule components. Overexpressing full-length PCIF1 inhibits stress granule formation, while PCIF1 knockout slows stress granule disassembly. PCIF1 binds mRNAs in their coding sequences (not cap-proximal regions) as shown by eCLIP, and this binding increases upon oxidative stress. ChIP-Seq shows PCIF1 association with transcription start sites rather than gene bodies, indicating PCIF1's association with mature mRNA is not co-transcriptional. Cell fractionation, immunofluorescence, co-immunoprecipitation with G3BP and stress granule components, eCLIP, ChIP-Seq, PCIF1 overexpression and knockout bioRxivpreprint Medium 38766247
2025 PCIF1 negatively regulates CD8+ T cell antitumor responses. PCIF1 KO elevates m6Am-modified ferroptosis suppressor gene transcripts (Fth1, Slc3a2) and the T cell activation gene Cd69, imparting resistance to ferroptosis and enhancing CD8+ T cell activation. Pcif1-deficient mice show enhanced responses to anti-PD-1 immunotherapy. Whole-body and T cell-specific Pcif1 KO mice, single-cell RNA-seq, proteomics, m6Am-sequencing, tumor growth assays, ferroptosis assays, CAR-T experiments Nature immunology High 39762445
2025 SERBP1 is a PCIF1 cofactor; the SERBP1-PCIF1 complex mediates m6Am deposition onto Maf1 mRNA in glutamatergic neurons. Increased PCIF1/SERBP1 adds m6Am to Maf1 mRNA, reduces MAF1 protein, and contributes to neuropathic pain and anxiety. Blocking SERBP1-PCIF1 upregulation abolishes m6Am gain on Maf1 and elevates MAF1. Co-immunoprecipitation (SERBP1-PCIF1 complex), m6Am-sequencing, conditional neuron-specific KO mice, AAV-mediated gene manipulation, behavioral pain assays Nature communications High 40764612
2025 The WW domain of PCIF1 is required for its inhibitory effect on glioma cell proliferation, independently of its methyltransferase activity. Forced nuclear expression of the WW domain reduces PCIF1 protein stability, diminishes PCIF1-RNA Pol II interaction, facilitates translocation of endogenous PCIF1 from nucleus to cytoplasm, and promotes PCIF1 degradation through the ubiquitin-proteasome system and autophagy-lysosomal pathway. Domain deletion/mutation analysis, overexpression of isolated WW domain, subcellular fractionation, Co-IP with RNA Pol II, proteasome/autophagy inhibitor assays, in vivo tumor models NPJ precision oncology Medium 41131141
2025 PCIF1 drives oesophageal squamous cell carcinoma (OSCC) progression by suppressing MTF2 translation via m6Am modification of MTF2 mRNA. Knockdown of PCIF1 reduces OSCC progression; MTF2 knockdown counteracts this effect, confirming the PCIF1-MTF2 epistatic axis. PCIF1 KO/knockdown in vitro and in vivo, m6Am analysis of MTF2 mRNA, translation assays, epistasis rescue (MTF2 KD), anti-PD1 combination in mouse model Clinical and translational medicine Medium 40156159
2026 PCIF1 modulates glioblastoma cell migration and invasion by regulating INPP5B levels: PCIF1 knockdown upregulates INPP5B (a PI5-phosphatase), causing PI(3,4)P2 accumulation and enhanced AKT activation, promoting EMT and invasion. PCIF1 overexpression increases PI(3,4,5)P3 and promotes proteasomal degradation of AKT while increasing p-AKT levels. PCIF1 overexpression and knockdown, EMT marker analysis, phosphoinositide measurements, AKT/p-AKT western blotting, proteasome inhibitor assays, migration/invasion assays Acta biochimica et biophysica Sinica Medium 42145053
2026 PCIF1 suppresses type I interferon induction in a methyltransferase-independent manner. PCIF1 attenuates IRF3 phosphorylation and nuclear translocation, suppressing IFNB1 transcription (increased nascent IFNB1 mRNA synthesis and promoter activity in PCIF1-deficient cells). Both wild-type PCIF1 and a methyltransferase-inactive mutant effectively suppress type I IFN induction. PCIF1 KO cells, poly(I:C) stimulation, IRF3 phosphorylation/nuclear translocation assays, nascent mRNA synthesis assay, promoter activity reporter, catalytically inactive PCIF1 rescue, STAT1 activation and ISG expression analysis Cells High 41677666
2026 GLI2 governs PCIF1 expression by binding the Pcif1 promoter. In the anterior cingulate cortex (ACC), PCIF1-mediated m6Am modification of Gap43 mRNA reduces GAP43 expression; loss of PCIF1 increases GAP43, leading to pre-LTP oversaturation and inflammatory pain/anxiety. Knockdown of GAP43 suppresses the pre-LTP oversaturation caused by PCIF1 reduction. Conditional Pcif1 KO in ACC neurons, m6Am-seq of Gap43 mRNA, chromatin immunoprecipitation (GLI2 on Pcif1 promoter), GAP43 knockdown epistasis, LTP recording, behavioral assays Cell reports High 41712381
2026 PCIF1-mediated m6Am modification is required for osteogenic differentiation of mesenchymal stem cells. Global or MSC-specific Pcif1 deletion causes osteoporosis in mice. PCIF1 stabilizes Wnt-related transcripts (Wnt11, Fzd4, Fgfr2) via m6Am modification; Pcif1 KO decreases their m6Am signals, accelerates mRNA degradation, downregulates active β-Catenin, and impairs osteogenesis. WNT agonist rescues the osteoporosis-like phenotype. Global and MSC-specific Pcif1 KO mice, m6Am-seq of Wnt-related mRNAs, mRNA stability assays, β-Catenin western blotting, WNT agonist rescue, bone phenotyping PLoS biology High 41941537

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Pcif1 modulates Pdx1 protein stability and pancreatic β cell function and survival in mice. The Journal of clinical investigation 78 20811152
2020 The Mammalian Cap-Specific m6Am RNA Methyltransferase PCIF1 Regulates Transcript Levels in Mouse Tissues. Cell reports 67 32814042
2004 Identification of PCIF1, a POZ domain protein that inhibits PDX-1 (MODY4) transcriptional activity. Molecular and cellular biology 53 15121856
2021 HIV reprograms host m6Am RNA methylome by viral Vpr protein-mediated degradation of PCIF1. Nature communications 52 34545078
2003 PCIF1, a novel human WW domain-containing protein, interacts with the phosphorylated RNA polymerase II. Biochemical and biophysical research communications 52 12565871
2022 Role of PCIF1-mediated 5'-cap N6-methyladeonsine mRNA methylation in colorectal cancer and anti-PD-1 immunotherapy. The EMBO journal 50 36514940
2022 m6Am methyltransferase PCIF1 is essential for aggressiveness of gastric cancer cells by inhibiting TM9SF1 mRNA translation. Cell discovery 49 35597784
2023 PCIF1-mediated deposition of 5'-cap N6,2'-O-dimethyladenosine in ACE2 and TMPRSS2 mRNA regulates susceptibility to SARS-CoV-2 infection. Proceedings of the National Academy of Sciences of the United States of America 34 36689652
2021 Methylation of viral mRNA cap structures by PCIF1 attenuates the antiviral activity of interferon-β. Proceedings of the National Academy of Sciences of the United States of America 34 34266951
2020 A novel circular RNA, circ-ATAD1, contributes to gastric cancer cell progression by targeting miR-140-3p/YY1/PCIF1 signaling axis. Biochemical and biophysical research communications 27 32169278
2023 The CTBP2-PCIF1 complex regulates m6Am modification of mRNA in head and neck squamous cell carcinoma. The Journal of clinical investigation 25 37643007
2025 The epitranscriptional factor PCIF1 orchestrates CD8+ T cell ferroptosis and activation to control antitumor immunity. Nature immunology 23 39762445
2019 CAPAM: The mRNA Cap Adenosine N6-Methyltransferase. Trends in biochemical sciences 21 30679132
2006 Two conserved domains in PCIF1 mediate interaction with pancreatic transcription factor PDX-1. FEBS letters 21 17126328
2022 Effects of the m6Am methyltransferase PCIF1 on cell proliferation and survival in gliomas. Biochimica et biophysica acta. Molecular basis of disease 17 35868483
2021 The cap-specific m6A methyltransferase, PCIF1/CAPAM, is dynamically recruited to the gene promoter in a transcription-dependent manner. Journal of biochemistry 16 33982754
2022 Enzymatic characterization of mRNA cap adenosine-N6 methyltransferase PCIF1 activity on uncapped RNAs. The Journal of biological chemistry 15 35189146
2021 A Pan-Cancer Analysis of the Oncogenic and Immunogenic Role of m6Am Methyltransferase PCIF1. Frontiers in oncology 15 34888238
2023 PCIF1, the only methyltransferase of N6,2-O-dimethyladenosine. Cancer cell international 14 37779183
2024 m6Am Methyltransferase PCIF1 Promotes LPP3 Mediated Phosphatidic Acid Metabolism and Renal Cell Carcinoma Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 13 39422663
2022 CAPturAM, a Chemo-Enzymatic Strategy for Selective Enrichment and Detection of Physiological CAPAM-Targets. Angewandte Chemie (International ed. in English) 12 36282111
2022 Enzymatic Characterization of In Vitro Activity of RNA Methyltransferase PCIF1 on DNA. Biochemistry 11 35605980
2024 m6Am methyltransferase PCIF1 negatively regulates ciliation by inhibiting BICD2 expression. The Journal of cell biology 8 38526325
2009 Prolyl isomerase Pin1 shares functional similarity with phosphorylated CTD interacting factor PCIF1 in vertebrate cells. Genes to cells : devoted to molecular & cellular mechanisms 6 19682092
2024 m6Am Methyltransferase PCIF1 Regulates Periodontal Inflammation. Journal of dental research 4 39290151
2025 SERBP1-PCIF1 complex-controlled m6Am modification in glutamatergic neurons of the primary somatosensory cortex is required for neuropathic pain in mice. Nature communications 3 40764612
2025 The WW domain presents a promising target for the development of PCIF1 agonists in the treatment of glioma. NPJ precision oncology 2 41131141
2024 Cap-Specific m6Am Methyltransferase PCIF1/CAPAM Regulates mRNA Stability of RAB23 and CNOT6 through the m6A Methyltransferase Activity. Cells 2 39451207
2023 Cap-specific terminal N6-methyladeonsine methylation of RNA mediated by PCIF1 and possible therapeutic implications. Genes & diseases 2 39524541
2025 PCIF1 drives oesophageal squamous cell carcinoma progression via m6Am-mediated suppression of MTF2 translation. Clinical and translational medicine 1 40156159
2025 Introduction of human m6Am methyltransferase PCIF1 facilitates the biosynthesis of terpenoids in Saccharomyces cerevisiae. Microbial cell factories 1 40176045
2024 LncRNA PCIF1 promotes aerobic glycolysis in A549/DDP cells by competitively binding miR-326 to regulate PKM expression. Molecular and cellular probes 1 39074568
2026 PCIF1 Attenuates Type I Interferon Induction by Inhibiting IRF3 Activation in a Methyltransferase-Independent Manner. Cells 0 41677666
2026 PCIF1-mediated m6Am modification in ACC neurons participates in inflammatory pain and anxiety. Cell reports 0 41712381
2026 The m6Am methyltransferase PCIF1 promotes osteogenic differentiation of mesenchymal stem cells through stabilization of Wnt-related transcripts. PLoS biology 0 41941537
2026 PCIF1 modulates glioblastoma cell migration and invasion by altering PI(3,4)P2 levels through the PI5-phosphatase INPP5B. Acta biochimica et biophysica Sinica 0 42145053
2024 PCIF1 is partly cytoplasmic, dynamically localizes to stress granules and binds mRNA coding regions upon oxidative stress. bioRxiv : the preprint server for biology 0 38766247

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