Affinage

PABPC3

Polyadenylate-binding protein 3 · UniProt Q9H361

Length
631 aa
Mass
70.0 kDa
Annotated
2026-06-10
22 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PABPC3 is a cytoplasmic poly(A)-binding protein that contributes to mRNA stabilization and translational control, with characterized roles in both the male germline and somatic cancer contexts (PMID:33744966, PMID:26843391). Its mRNA-binding activity is regulated post-translationally: the E3 ligase MKRN3 ubiquitinates PABPC3 (together with PABPC1 and PABPC4), attenuating poly(A) tail binding, shortening the poly(A) tail of GNRH1 mRNA, and impairing translation initiation complex formation (PMID:33744966). In testis, PABPC3 protein is cytoplasmic in spermatocytes and round spermatids, and its rodent ortholog PABPC2 is enriched in chromatoid bodies; however, combined loss of the testis-specific PABPCs does not impair testicular protein synthesis or spermatogenesis, indicating functional redundancy with co-existing PABPC proteins including PABPC1 (PMID:26843391, PMID:38281153, PMID:40254460). In ovarian cancer, PABPC3 drives proliferation, migration, and metastasis, acting at least in part by downregulating the tight-junction component CLDN1, since CLDN1 knockdown partially rescues the migration phenotype caused by PABPC3 depletion (PMID:41249135).

Mechanistic history

Synthesis pass · year-by-year structured walk · 5 steps
  1. 2015 Low

    Established a candidate RNA-interaction partner for PABPC3, beginning to define its binding repertoire beyond bulk poly(A) mRNA.

    Evidence MS2-tagged RNA affinity purification and mass spectrometry identifying PABPC3 binding to lncRNA MEG3

    PMID:26155902

    Open questions at the time
    • No functional consequence of the MEG3 interaction established
    • Single pulldown-based method from one lab
    • Does not address whether binding is direct or bridged
  2. 2016 Low

    Defined the spatial and developmental expression of PABPC3 in human testis, implicating it in germ-cell mRNA control.

    Evidence Immunohistochemistry and fraction-based protein/mRNA quantification in testicular biopsies across spermatogenic defects

    PMID:26843391

    Open questions at the time
    • No functional manipulation to test a causal role
    • Correlation with disease state does not establish mechanism
    • Target mRNAs in germ cells not identified
  3. 2021 Medium

    Identified a post-translational regulatory mechanism controlling PABPC3 activity, linking ubiquitination to poly(A) binding and translation initiation.

    Evidence Ubiquitination assays, poly(A) tail-length measurement, and translation initiation complex analysis showing MKRN3 ubiquitinates PABPC3 and shortens GNRH1 poly(A) tails

    PMID:33744966

    Open questions at the time
    • Not independently replicated
    • Ubiquitination sites on PABPC3 and stoichiometry unresolved
    • GNRH1 is the only target mRNA examined
  4. 2024 Medium

    Tested whether testis-specific PABPC localization translates to an essential germline function, addressing the redundancy question.

    Evidence Immunostaining, polysome fractionation, and PABPC2/PABPC6 double-knockout mouse phenotyping

    PMID:38281153

    Open questions at the time
    • Rodent ortholog rather than human PABPC3
    • Poor polysome association leaves its translational substrate unclear
    • Redundancy partners not enumerated mechanistically
  5. 2025 Medium

    Confirmed germline redundancy and demonstrated a distinct, non-redundant role for PABPC3 in tumor progression with a defined downstream effector.

    Evidence Double-knockout mouse fertility analysis (PABPC2/PABPC6); siRNA/overexpression in ovarian cancer cells with in vivo metastasis and CLDN1 epistasis

    PMID:40254460 PMID:41249135

    Open questions at the time
    • Mechanism connecting PABPC3 to CLDN1 downregulation not defined
    • Rescue by CLDN1 knockdown is only partial, implying additional effectors
    • Cancer role examined in single labs per tumor type

Open questions

Synthesis pass · forward-looking unresolved questions
  • How PABPC3's poly(A)-binding/translational activity mechanistically couples to its pro-tumorigenic effects and which mRNAs it regulates in each tissue remain unresolved.
  • No transcriptome-wide map of PABPC3-bound or regulated mRNAs in cancer cells
  • Whether MKRN3-mediated regulation operates in somatic/tumor contexts is untested
  • Direct vs indirect basis of CLDN1 downregulation unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 2
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-8953854 Metabolism of RNA 1
Partners
MEG3MKRN3
Complex memberships
chromatoid body

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2021 PABPC3 is a substrate for MKRN3-mediated ubiquitination; MKRN3-mediated ubiquitination of PABPC3 (along with PABPC1 and PABPC4) attenuates binding of PABPs to poly(A) tails of mRNA, leading to shortened poly(A) tail-length of GNRH1 mRNA and compromised formation of the translation initiation complex (TIC). Biochemical substrate identification, ubiquitination assay, poly(A) tail-length measurement, translation initiation complex analysis Nucleic acids research Medium 33744966
2015 PABPC3 (cytoplasmic poly(A)-binding protein 3) physically interacts with the lncRNA MEG3, as validated by MS2-tagged RNA affinity purification and mass spectrometry (MTRAP-MS). MS2-tagged RNA affinity purification followed by mass spectrometry (MTRAP-MS); interaction validated independently Applied biochemistry and biotechnology Low 26155902
2016 PABPC3 protein is cytoplasmically localized in spermatocytes and round spermatids in human testis; its expression is progressively reduced from hypospermatogenesis to Sertoli cell-only syndrome, implicating it in mRNA stabilization/translational control during spermatogenesis. Immunohistochemistry/immunofluorescence localization in testicular biopsy samples; mRNA and protein quantification in isolated spermatocyte and round spermatid fractions Journal of assisted reproduction and genetics Low 26843391
2024 Mouse PABPC2 (the rodent ortholog of primate PABPC3) localizes to the cytoplasm of pachytene spermatocytes and is enriched in chromatoid bodies of round spermatids; it barely associates with translationally active polysomes; double knockout of PABPC2 and PABPC6 does not affect testicular protein synthesis or spermatogenesis, indicating functional redundancy with other co-existing PABPC proteins. Protein localization by immunostaining, polysome fractionation, genetic knockout (double mutant mice), assessment of spermatogenesis and fertility Biology of reproduction Medium 38281153
2025 Mice lacking both PABPC2 and PABPC6 (the two rodent testis-specific PABPCs; PABPC2 is the rodent ortholog of human PABPC3) show no defect in testicular protein synthesis, spermatogenesis, or male fertility, confirming functional redundancy with co-existing PABPC proteins including PABPC1. Double-mutant mouse knockout, testicular protein synthesis assessment, spermatogenesis and fertility analysis The Journal of reproduction and development Medium 40254460
2025 PABPC3 promotes ovarian cancer cell proliferation and migration in vitro and enhances metastatic potential in vivo; mechanistically, PABPC3 downregulates expression of the tight-junction component CLDN1, and simultaneous CLDN1 knockdown partially rescues the migration-inhibitory effects of PABPC3 depletion. siRNA knockdown and overexpression of PABPC3 in ovarian cancer cell lines (MTT, EdU, Transwell assays); in vivo metastasis models; CLDN1 expression measurement; double-knockdown epistasis experiment Cell death & disease Medium 41249135
2023 PABPC3 knockdown inhibits proliferation and migration of osteosarcoma cells in vitro, while overexpression has the opposite effect, establishing a functional role for PABPC3 in osteosarcoma tumor progression. siRNA knockdown and overexpression in osteosarcoma cell lines; MTT, EdU, and Transwell assays The journal of gene medicine Low 38058264

Source papers

Stage 0 corpus · 22 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2021 MKRN3-mediated ubiquitination of Poly(A)-binding proteins modulates the stability and translation of GNRH1 mRNA in mammalian puberty. Nucleic acids research 67 33744966
2019 Analysis of head and neck carcinoma progression reveals novel and relevant stage-specific changes associated with immortalisation and malignancy. Scientific reports 37 31427592
2021 DNA methylome in visceral adipose tissue can discriminate patients with and without colorectal cancer. Epigenetics 24 34311674
2015 Identification of lncRNA MEG3 Binding Protein Using MS2-Tagged RNA Affinity Purification and Mass Spectrometry. Applied biochemistry and biotechnology 24 26155902
2018 Whole-Exome Sequencing Identifies Two Discrete Druggable Signaling Pathways in Follicular Thyroid Cancer. Journal of the American College of Surgeons 21 29571661
2016 The poly(A)-binding protein genes, EPAB, PABPC1, and PABPC3 are differentially expressed in infertile men with non-obstructive azoospermia. Journal of assisted reproduction and genetics 19 26843391
2023 Human Tissues Exhibit Diverse Composition of Translation Machinery. International journal of molecular sciences 13 37176068
2022 Establishment and characterization of the third non-functional human pancreatic neuroendocrine tumor cell line. Human cell 13 35394261
2021 Whole-exome sequencing reveals potential germline and somatic mutations in 60 malignant ovarian germ cell tumors†. Biology of reproduction 13 33739378
2022 The genomic landscape of Cronkhite-Canada syndrome: Possible clues for pathogenesis. Journal of digestive diseases 12 35678525
2022 Integration of gene co-expression analysis and multi-class SVM specifies the functional players involved in determining the fate of HTLV-1 infection toward the development of cancer (ATLL) or neurological disorder (HAM/TSP). PloS one 9 35041720
2022 Identification of Potentially Pathogenic Variants Associated with Recurrence in Medication-Related Osteonecrosis of the Jaw (MRONJ) Patients Using Whole-Exome Sequencing. Journal of clinical medicine 9 35456240
2016 In silico analysis of candidate proteins sharing homology with Streptococcus agalactiae proteins and their role in male infertility. Systems biology in reproductive medicine 7 27802063
2022 Whole-exome sequencing of epithelial ovarian carcinomas differing in resistance to platinum therapy. Life science alliance 6 36229065
2020 Whole Exome Sequencing of Multiple Atypical Meningiomas in a Patient without History of Neurofibromatosis Type II: A Case Report. The American journal of case reports 5 32461543
2023 Disulfidptosis-related PABPC3 promotes tumor progression and inhibits immune activity in osteosarcoma. The journal of gene medicine 4 38058264
2025 Whole Exome Sequencing Study Identifies Distinct Characteristics of Transformed Small Cell Lung Cancer With EGFR Mutation Compared to De Novo Small Cell and Primary Non-Small Cell Lung Cancers. Cancer medicine 3 40197849
2024 Intronless Pabpc6 encodes a testis-specific, cytoplasmic poly(A)-binding protein but is dispensable for spermatogenesis in the mouse†. Biology of reproduction 2 38281153
2024 Network Pharmacology Approaches Used to Identify Therapeutic Molecules for Chronic Venous Disease Based on Potential miRNA Biomarkers. Journal of xenobiotics 1 39449424
2025 Mice lacking two testis-specific cytoplasmic poly(A)-binding proteins, PABPC2 and PABPC6, exhibit normal spermatogenesis and fertility. The Journal of reproduction and development 0 40254460
2025 Association of Fc gamma-binding protein rs1464897604 polymorphism with bronchiolitis obliterans syndrome in lung transplant recipients. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation 0 40441397
2025 PABPC3 drives ovarian cancer metastasis and drug sensitivity by downregulating CLDN1 expression. Cell death & disease 0 41249135

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