Affinage

PAN2

Retinol dehydrogenase 14 · UniProt Q9HBH5

Length
336 aa
Mass
36.9 kDa
Annotated
2026-06-10
31 papers in source corpus 20 papers cited in narrative 20 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/7 claims corpus-supported (71%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PAN2 is the catalytic engine of two distinct activities: it serves as the deadenylase subunit of the PAN2-PAN3 complex that shortens mRNA poly(A) tails, and it acts as a deubiquitinase (USP52) that stabilizes diverse protein substrates (PMID:8550599, PMID:29599486). As a poly(A) nuclease, PAN2 was first defined in yeast where its deletion abolishes poly(A)-binding-protein-stimulated nuclease activity and lengthens mRNA poly(A) tails in vivo (PMID:8550599). Structural and biochemical work established that PAN2 partners with a PAN3 pseudokinase homodimer in 1:2 stoichiometry; PAN3 binds poly(A) RNA and the PAN2 linker, supplying substrate and orienting the PAN2 nuclease active site, so that the reconstituted complex deadenylates RNA independently of poly(A)-binding protein (PMID:24872509, PMID:24880344). PAN2 recognizes the intrinsic stacked, helical conformation of poly(A) rather than base-specific contacts, and engages poly(A) RNPs bearing two or more PABP/PABPC1 protomers that act as molecular rulers threading the tail into the active site (PMID:31110294, PMID:31104843); the human complex has an extended substrate-binding path matched to the longer mammalian poly(A) tails (PMID:41275497). Recruitment to specific transcripts occurs through GW182/TNRC6 proteins for miRNA targets and through RNA-binding-protein adaptors such as MEX3, YTHDF and ZFP36 (PMID:23932717). In a separate enzymatic role, the USP52 catalytic activity removes K48- or K11-linked ubiquitin chains to stabilize substrates including the histone chaperone ASF1A, supporting chromatin assembly, and CtIP, whose deubiquitination promotes DNA end resection and homologous recombination and is enhanced by ATM-mediated phosphorylation of USP52 at Ser-1003 after DNA damage (PMID:29599486, PMID:33097710). Germline deletion of Pan2 in mice arrests spermatogenesis, disrupts round-spermatid poly(A) homeostasis and reduces translation efficiency, with PAN2 associating with PABPC1 and translation initiation factors (PMID:41714623).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1996 High

    Established PAN2 as the catalytic subunit responsible for poly(A)-binding-protein-stimulated poly(A) nuclease activity, defining its core function in mRNA tail shortening.

    Evidence Yeast PAN2 gene deletion with in vitro PAN assays in crude extracts and in vivo poly(A) tail length measurement

    PMID:8550599

    Open questions at the time
    • Did not resolve how PAN2 is recruited to substrates
    • No structural basis for catalysis
  2. 2002 Medium

    Linked the PAN2-PAN3 deadenylase to post-transcriptional control of DNA repair gene expression, an early functional context beyond bulk mRNA turnover.

    Evidence Yeast two-hybrid/genetic interaction of Dun1 with Pan3, double-mutant stress sensitivity, and RAD5 mRNA Northern analysis

    PMID:11953437

    Open questions at the time
    • Mechanistic basis of selective RAD5 regulation unresolved
    • Interaction mapped to Pan3, not Pan2 directly
  3. 2013 High

    Defined the structural basis for PAN3 homodimerization, PAN2 binding, and recruitment to miRNA targets via GW182/TNRC6 proteins.

    Evidence PAN3 crystal structure with mutagenesis, co-IP with TNRC6C, and in vivo mRNA degradation assays

    PMID:23932717

    Open questions at the time
    • Did not capture the PAN2 catalytic domain architecture
    • Recruitment beyond miRNA pathway not addressed
  4. 2013 Medium

    Revealed an unexpected second activity — that the human protein (USP52) localizes to P-bodies and stabilizes a specific mRNA in a poly(A)-independent, 3'-UTR-dependent manner.

    Evidence siRNA knockdown, HIF1A 3'-UTR luciferase reporter, co-localization imaging, and affinity-purification mass spectrometry

    PMID:23398456

    Open questions at the time
    • Did not reconcile mRNA-stabilizing role with deadenylase activity
    • Direct RNA target binding not demonstrated
  5. 2014 High

    Determined how PAN3 supplies RNA substrate to PAN2 and the architecture/stoichiometry of the core complex, explaining catalytic enhancement.

    Evidence Crystal structures of the Pan2 linker–Pan3 dimer and the Pan2-Pan3 core, RNA-binding and stoichiometry assays, in vitro deadenylation

    PMID:24872509 PMID:24880344

    Open questions at the time
    • How poly(A) is recognized by the nuclease itself not yet defined
    • PABP contribution structurally uncharacterized
  6. 2019 High

    Showed PAN2 reads the intrinsic stacked conformation of poly(A) and that PABP oligomers serve as length rulers feeding RNA into the active site.

    Evidence Crystal structures of Pan2-RNA and cryo-EM of Pan2-Pan3 with poly(A)-Pab1 RNP, plus reconstituted deadenylation with modified substrates

    PMID:31104843 PMID:31110294

    Open questions at the time
    • Did not address mammalian-specific substrate features
    • Adaptor-mediated recruitment not modeled
  7. 2018 Medium

    Established USP52/PAN2 as a bona fide deubiquitinase, stabilizing ASF1A to support chromatin assembly and cell cycle progression.

    Evidence Reciprocal Co-IP, in vivo ubiquitination assays, and knockdown/overexpression with chromatin and cell cycle readouts

    PMID:29599486

    Open questions at the time
    • Catalytic residues for DUB activity not mapped here
    • Relationship between deadenylase and DUB activities unresolved
  8. 2020 High

    Connected USP52 DUB activity to the DNA damage response, showing it deubiquitinates CtIP to enable resection and HR, and is itself activated by ATM phosphorylation.

    Evidence Co-IP, in vitro/in vivo deubiquitination assays, Thr-847 and Ser-1003 mutagenesis, HR and PARP-inhibitor sensitivity assays

    PMID:33097710

    Open questions at the time
    • Ubiquitin chain linkage on CtIP not specified
    • Whether deadenylase function contributes to HR not tested
  9. 2024 Medium

    Extended the USP52 substrate repertoire to ferroptosis control, stabilizing xCT/SLC7A11 by cleaving K48 chains at defined lysines.

    Evidence siRNA screen, Co-IP, K48-specific ubiquitination assay with K4/K12 mutagenesis, ferroptosis assays, and xenografts

    PMID:39392373

    Open questions at the time
    • Generality across cancer types not established
    • Regulation of USP52 selectivity for xCT unknown
  10. 2025 Medium

    Broadened substrate-targeting of the deadenylase, showing RNA-binding-protein adaptors (MEX3, YTHDF, ZFP36) recruit PAN2-PAN3 beyond canonical PABP-mediated engagement.

    Evidence Biochemical reconstitution/binding assays and cell affinity purification (preprint)

    PMID:bio_10.1101_2025.09.27.678968

    Open questions at the time
    • Structural basis of adaptor binding not resolved
    • Preprint, not peer-reviewed
  11. 2025 High

    Defined human-specific deadenylase mechanics and additional DUB substrates linking USP52 to YAP/Hippo and ferroptosis.

    Evidence Cryo-EM of human PAN2-PAN3 on long poly(A)-PABPC1 substrates with deadenylation assays; Co-IP and K11-specific ubiquitination assays for YAP

    PMID:40962058 PMID:41275497

    Open questions at the time
    • Functional consequences of the extended human substrate path in vivo untested
    • How USP52 chooses K11 vs K48 substrates unclear
  12. 2026 High

    Demonstrated a physiological requirement for PAN2 in spermatogenesis through poly(A) homeostasis and translational support, alongside continued expansion of DUB substrates.

    Evidence Germline conditional Pan2 knockout mouse with PAIso-seq2, Ribo-lite, and IP-MS; Co-IP/ubiquitination/rescue and xenograft studies for CORO6, RBM5, and RAB11FIP5

    PMID:41714623 PMID:41894088 PMID:42033890 PMID:42207639

    Open questions at the time
    • Whether spermatogenic phenotype reflects deadenylase or DUB activity unresolved
    • Most cancer DUB substrates studied in single lineages

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein partitions between its poly(A) deadenylase and protein deubiquitinase activities — including whether the same catalytic chemistry, distinct domains, or regulatory inputs govern each — remains unresolved.
  • No structure of USP52 DUB-substrate complex
  • Determinants of substrate/activity choice unknown
  • In vivo balance of the two functions uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140098 catalytic activity, acting on RNA 5 GO:0140096 catalytic activity, acting on a protein 4 GO:0003723 RNA binding 3 GO:0016787 hydrolase activity 3
Localization
GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953854 Metabolism of RNA 3 R-HSA-73894 DNA Repair 1
Partners
ASF1ACTIPPABPC1PAN3RBM5SLC7A11TNRC6CYAP
Complex memberships
PAN2-PAN3 deadenylase complex

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 Pan2p (yeast ortholog of PAN2) is the catalytic subunit required for poly(A)-binding protein (Pab1p)-stimulated poly(A) nuclease (PAN) activity; deletion of PAN2 abolishes Pab1p-stimulated PAN activity in crude extracts and increases average mRNA poly(A) tail length in vivo. Gene deletion, in vitro enzymatic assay with crude extracts, in vivo poly(A) tail length analysis The Journal of biological chemistry High 8550599
2013 PAN3 forms intertwined, asymmetric homodimers whose knob domain is required for binding PAN2; a tryptophan-binding pocket at the PAN3 dimer interface mediates interaction with GW182/TNRC6C proteins, providing the structural basis for recruitment of PAN2-PAN3 to miRNA targets. Crystal structure of PAN3, mutagenesis of binding surfaces, co-immunoprecipitation with TNRC6C, in vivo mRNA degradation assays Molecular cell High 23932717
2014 Pan3 binds poly(A) RNA directly through its pseudokinase/C-terminal domain and an N-terminal zinc finger (poly(A)-specific), while isolated Pan2 cannot bind RNA; Pan3 binds the linker region of Pan2 (between WD40 and exonuclease domains) with 2:1 (Pan3 dimer:Pan2) stoichiometry, supplying Pan2 with poly(A) substrate to enable efficient deadenylation. Crystal structure of Pan2 linker bound to Pan3 homodimer, RNA binding assays, stoichiometry analysis, in vitro deadenylation assay The EMBO journal High 24872509
2014 The Pan2-Pan3 core complex (yeast) has a 1:2 stoichiometry (one Pan2 per Pan3 homodimer); an extended Pan2 region wraps around Pan3, and a Pan2 module composed of the pseudoubiquitin-hydrolase and RNase domains latches onto the Pan3 pseudokinase, orienting the deadenylase active site toward the poly(A)-binding site of Pan3; the complex can deadenylate RNA in vitro without Pab1. Crystal structure of ~200-kDa core complex, in vitro deadenylation assay with recombinant proteins Nature structural & molecular biology High 24880344
2019 Pan2 recognizes the intrinsic stacked, helical conformation of poly(A) RNA rather than making canonical base-specific contacts; disruption of this poly(A) structure (e.g., by incorporation of guanosine) inhibits deadenylation by Pan2 in a fully reconstituted biochemical system. Crystal structures of S. cerevisiae Pan2 in complex with RNA, fully reconstituted in vitro deadenylation assay with modified RNA substrates Nature structural & molecular biology High 31110294
2019 Pan2-Pan3 associates with and degrades poly(A) RNPs containing two or more Pab1 molecules; cryo-EM structure of Pan2-Pan3 in complex with poly(A) RNP (90 nt poly(A) + three Pab1 protomers) shows that Pab1 oligomerization interfaces are recognized by conserved features of the deadenylase, which threads the poly(A) RNA into the nuclease active site; Pab1 oligomers act as rulers for poly(A) tail length. In vitro reconstitution with recombinant proteins, cryo-EM structure, in vitro deadenylation assay Cell High 31104843
2013 USP52/PAN2 localizes to cytoplasmic P-bodies and is required to stabilize HIF1A mRNA; depletion of USP52 causes 3'-UTR-dependent, poly(A)-tail-length-independent destabilization of HIF1A mRNA; USP52 associates with multiple P-body components as shown by MS. siRNA knockdown, luciferase reporter assay with HIF1A 3'-UTR, co-localization imaging, mass spectrometry (affinity purification), qRT-PCR for mRNA levels The Biochemical journal Medium 23398456
2018 USP52/PAN2 functions as a bona fide deubiquitinase (ubiquitin-specific protease): it physically associates with histone chaperone ASF1A, promotes ASF1A deubiquitination and protein stabilization, and thereby facilitates chromatin assembly and cell cycle progression. Co-immunoprecipitation, ubiquitination assays, knockdown/overexpression with cell cycle and chromatin assembly readouts Nature communications Medium 29599486
2020 USP52 directly interacts with and deubiquitinates CtIP, removing inhibitory ubiquitination to facilitate CtIP phosphorylation at Thr-847 and activation of DNA end resection and homologous recombination; ATM phosphorylates USP52 at Ser-1003 after DNA damage to enhance USP52 catalytic activity. Co-immunoprecipitation, in vivo and in vitro ubiquitination/deubiquitination assays, site-directed mutagenesis (Thr-847, Ser-1003), DNA end resection and HR assays, PARP inhibitor sensitivity assays in vitro and in vivo Nature communications High 33097710
2002 The Dun1 kinase forkhead-associated domain physically interacts with the Pan3 subunit of the Pan2-Pan3 poly(A) nuclease complex; dun1Δpan2Δ double mutants show hypersensitivity to replicational stress and specific up-regulation of RAD5, indicating that Dun1 and Pan2-Pan3 cooperate in post-transcriptional regulation of DNA repair gene stoichiometry. Yeast two-hybrid / genetic interaction, double-mutant phenotypic analysis (sensitivity to HU/MMS), Northern blot for RAD5 mRNA levels, overexpression epistasis The Journal of biological chemistry Medium 11953437
2024 USP52 interacts with xCT (SLC7A11) and enzymatically cleaves K48-conjugated ubiquitin chains at K4 and K12 of xCT, enhancing xCT protein stability and thereby suppressing ferroptosis by maintaining glutathione synthesis in bladder cancer cells. siRNA screen, co-immunoprecipitation, in vivo ubiquitination assay with K48-specific ubiquitin, mutagenesis of K4/K12 on xCT, ferroptosis assays, xenograft mouse model Advanced science Medium 39392373
2025 USP52 deubiquitinates YAP by removing K11-linked ubiquitin chains, stabilizing YAP protein and activating its transcriptional targets (CTGF, CYR61), thereby suppressing ferroptosis through Hippo-YAP signaling in colorectal cancer cells. Co-immunoprecipitation, ubiquitination assay (K11-linkage specific), knockdown/overexpression with YAP target gene expression and ferroptosis assays, in vivo tumor models The Journal of biological chemistry Medium 40962058
2025 Human PAN2-PAN3 shows preferential deadenylase activity on long poly(A)-PABPC1 ribonucleoprotein substrates; cryo-EM structures reveal a longer substrate-binding path in the human complex compared to the fungal counterpart, providing a mechanistic basis for co-evolution of deadenylase activity with longer poly(A) tails characteristic of mammalian mRNAs. In vitro reconstitution with defined poly(A) RNA substrates (up to 240 nt), single-particle cryo-EM, deadenylation activity assays Cell reports High 41275497
2026 In mice, germline-specific deletion of Pan2 causes male infertility due to spermatogenic arrest at step 8/9; PAN2 maintains poly(A) tail homeostasis in round spermatids, and its loss reduces global translation efficiency; PAN2 associates with PABPC1 and initiation factors EIF4E, EIF4A1, and EIF5A (identified by endogenous IP-MS), whose protein levels decline upon Pan2 loss. Conditional knockout mouse model, PAIso-seq2 for poly(A) tail profiling, Ribo-lite for translation efficiency, mass spectrometry, endogenous IP-MS Nature communications High 41714623
2021 In yeast, Pan2 and Pan3 are phosphorylated when cells are switched to non-fermentable carbon sources, suggesting activity regulation by phosphorylation; ccr4Δpan2Δ double mutants fail to grow on non-fermentable carbon sources while ccr4Δ single mutants can, indicating a specific cooperative role of Pan2-Pan3 with Ccr4-Not in this context. Gene deletion, growth assays on non-fermentable carbon media, phosphorylation analysis, multicopy suppressor screen Biochemical and biophysical research communications Low 34280615
2025 PAN2-PAN3 can be recruited to specific mRNA targets via RNA-binding protein adaptors (MEX3, YTHDF, ZFP36), in addition to its canonical recruitment via poly(A)-binding protein; biochemical reconstitution showed direct interaction of these RBPs with PAN2-PAN3, and in cells a diverse range of RNA adaptors interact with both PAN2-PAN3 and CCR4-NOT. Biochemical reconstitution (pulldown/binding assays), affinity purification from cells, interaction assays bioRxivpreprint Medium bio_10.1101_2025.09.27.678968
2021 USP52 stabilizes PTEN protein in NSCLC cells; depletion of USP52 reduces PTEN stability and activates AKT/mTOR signaling and cyclin D1 expression, inhibiting cell proliferation. siRNA knockdown, Western blot for PTEN protein levels, cell proliferation assays, AKT/mTOR pathway readouts Bioscience reports Low 34533198
2026 USP52 interacts with CORO6 and decreases its K48-linked ubiquitination, preventing CORO6 proteasomal degradation in clear cell renal carcinoma cells; USP52 knockdown reduces CORO6 protein levels and impairs malignant cell behaviors that are rescued by CORO6 overexpression. Co-immunoprecipitation, ubiquitination assay (K48-specific), knockdown/overexpression with rescue experiments, xenograft mouse model Translational oncology Medium 42033890
2026 USP52 deubiquitinates RBM5 to stabilize it; stabilized RBM5 interacts with the NCAPG2 3'-UTR to down-regulate NCAPG2 expression, suppressing prostate cancer cell proliferation, migration, invasion, and stemness. Co-immunoprecipitation, ubiquitination assay, dual-luciferase reporter assay (RBM5-NCAPG2 3'UTR interaction), knockdown/overexpression, xenograft tumor assay Molecular and cellular biochemistry Medium 41894088
2026 USP52 stabilizes RAB11FIP5 by cleaving K48-linked ubiquitin chains at lysine residues K583 and K586; stabilized RAB11FIP5 competitively sequesters RAB11A to antagonize RAB11FIP1-mediated transferrin receptor recycling, reducing iron uptake and suppressing ferroptosis in head and neck squamous cell carcinoma. Co-immunoprecipitation, ubiquitination assay (K48-specific, site mutagenesis), transferrin recycling assays, siRNA knockdown, xenograft mouse model Cell reports Medium 42207639

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 RNA decay machines: deadenylation by the Ccr4-not and Pan2-Pan3 complexes. Biochimica et biophysica acta 197 23337855
1996 The yeast Pan2 protein is required for poly(A)-binding protein-stimulated poly(A)-nuclease activity. The Journal of biological chemistry 153 8550599
2013 Structure of the PAN3 pseudokinase reveals the basis for interactions with the PAN2 deadenylase and the GW182 proteins. Molecular cell 84 23932717
2019 Molecular Basis for poly(A) RNP Architecture and Recognition by the Pan2-Pan3 Deadenylase. Cell 82 31104843
2012 Identification of PAN2 by quantitative proteomics as a leucine-rich repeat-receptor-like kinase acting upstream of PAN1 to polarize cell division in maize. The Plant cell 76 23175742
2014 Structural basis for Pan3 binding to Pan2 and its function in mRNA recruitment and deadenylation. The EMBO journal 55 24872509
2019 The intrinsic structure of poly(A) RNA determines the specificity of Pan2 and Caf1 deadenylases. Nature structural & molecular biology 50 31110294
2013 The P-body component USP52/PAN2 is a novel regulator of HIF1A mRNA stability. The Biochemical journal 50 23398456
2014 mRNA deadenylation by Pan2-Pan3. Biochemical Society transactions 49 24450649
2014 The structure of the Pan2-Pan3 core complex reveals cross-talk between deadenylase and pseudokinase. Nature structural & molecular biology 46 24880344
2012 The Caenorhabditis elegans GW182 protein AIN-1 interacts with PAB-1 and subunits of the PAN2-PAN3 and CCR4-NOT deadenylase complexes. Nucleic acids research 44 22402495
2018 USP52 acts as a deubiquitinase and promotes histone chaperone ASF1A stabilization. Nature communications 42 29599486
2002 Human pancreas protein 2 (PAN2) has a retinal reductase activity and is ubiquitously expressed in human tissues. FEBS letters 35 12435598
2002 Posttranscriptional regulation of the RAD5 DNA repair gene by the Dun1 kinase and the Pan2-Pan3 poly(A)-nuclease complex contributes to survival of replication blocks. The Journal of biological chemistry 33 11953437
2020 USP52 regulates DNA end resection and chemosensitivity through removing inhibitory ubiquitination from CtIP. Nature communications 30 33097710
2024 Deubiquitylase USP52 Promotes Bladder Cancer Progression by Modulating Ferroptosis through Stabilizing SLC7A11/xCT. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 39392373
2014 Divergent roles for maize PAN1 and PAN2 receptor-like proteins in cytokinesis and cell morphogenesis. Plant physiology 26 24578508
2023 Stomatal closure in maize is mediated by subsidiary cells and the PAN2 receptor. The New phytologist 16 37936339
2021 USP52 inhibits cell proliferation by stabilizing PTEN protein in non-small cell lung cancer. Bioscience reports 12 34533198
2022 Biallelic PAN2 variants in individuals with a syndromic neurodevelopmental disorder and multiple congenital anomalies. European journal of human genetics : EJHG 9 35304602
2025 USP52 inhibits cell ferroptosis via Hippo-YAP pathway and blocks immunotherapy in colorectal cancer. The Journal of biological chemistry 2 40962058
2021 Pan2-Pan3 complex, together with Ccr4-Not complex, has a role in the cell growth on non-fermentable carbon sources. Biochemical and biophysical research communications 2 34280615
2019 Author Correction: The intrinsic structure of poly(A) RNA determines the specificity of Pan2 and Caf1 deadenylases. Nature structural & molecular biology 2 31420603
2025 Novel Missense Variant in the PAN2 Gene Associated With Congenital Anomalies and Neurodevelopmental Delay: Expanding the Phenotypic and Mutational Spectrum of PAN2-Related Disorders. Birth defects research 1 40491293
2026 Pan2-Pan3 Complex-Mediated Deadenylation Enforces mRNA Quality Control for Infection of the Rice Blast Fungus. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 0 41556236
2026 PAN2 maintains mRNA poly(A) tail homeostasis and regulates translation during spermiogenesis in mice. Nature communications 0 41714623
2026 USP52 impedes malignant progression and cell stemness in prostate cancer by deubiquitinating RBM5 to down-regulate NCAPG2. Molecular and cellular biochemistry 0 41894088
2026 USP52 promotes clear cell renal carcinoma progression by deubiquitinating and stabilizing CORO6. Translational oncology 0 42033890
2026 Further delineation of the phenotype and genotype in a newly identified PAN2-related disorder. Journal of human genetics 0 42151529
2026 USP52-RAB11FIP5 axis suppresses ferroptosis by repressing transferrin receptor recycling in head and neck squamous cell carcinoma. Cell reports 0 42207639
2025 Mechanisms governing poly(A)-tail-length specificity of the human PAN2-PAN3 deadenylase complex. Cell reports 0 41275497

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