ArticleCancer communications (London, England)2021
Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C.
Article in Cancer communications (London, England), 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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13 citing papers in PubMed, 17 citations in OpenAlex.
- Yiyi Fuzi Baijiang formula protects against DSS-induced colitis by orchestrating the gut barrier-microbiota-metabolism axis.Chinese medicine · 2026Article
- Renaissance of Traditional Mineral Drugs in Cancer: Advanced Delivery Strategies and Bioengineering Approaches.Pharmaceutics · 2026Review
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- FAM46C Expression Sensitizes Multiple Myeloma Cells to PF-543-Induced Cytotoxicity.Biomolecules · 2025Article
- Bevacizumab in ovarian cancer therapy: current advances, clinical challenges, and emerging strategies.Frontiers in bioengineering and biotechnology · 2025Review
- TENT5A Increases Glioma Malignancy and Promotes its Progression.Recent patents on anti-cancer drug discovery · 2025Article
- Identification and Validation of New DNA-PKcs Inhibitors through High-Throughput Virtual Screening and Experimental Verification.International journal of molecular sciences · 2024Article
- Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance.Cancers · 2024Review
- ITGAX promotes gastric cancer progression via epithelial-mesenchymal transition pathway.Frontiers in pharmacology · 2024Article
- Inhibition of FAM46/TENT5 activity by BCCIPα adopting a unique fold.Science advances · 2023Article
- Multiple myeloma with high-risk cytogenetics and its treatment approach.International journal of hematology · 2022Review
- Review
- Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C.Cancer communications (London, England) · 2021Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundMultiple myeloma (MM) is a hematologic malignancy characterized by the accumulation of aberrant plasma cells within the bone marrow. The high frequent mutation of family with sequence similarity 46, member C (FAM46C) is closely related with the occurrence and progression of MM. Recently, FAM46C has been identified as a non-canonical poly(A) polymerase (PAP) that functions as a tumor suppressor in MM. This study aimed to elucidate the structural features of this novel non-canonical PAP and how MM-related mutations affect the structural and biochemical properties of FAM46C, eventually advancing our understandings towards FAM46C mutation-related MM occurrence.
methodsWe purified and crystallized a mammalian FAM46C construct, and solved its structure. Next, we characterized the property of FAM46C as a PAP through a combination of structural analysis, site-directed mutagenesis and biochemical assays, and by comparison with its homolog FAM46B. Finally, we structurally analyzed MM-related FAM46C mutations and tested the enzymatic activity of corresponding mutants.
resultsWe determined the crystal structure of a mammalian FAM46C protein at 2.35 Å, and confirmed that FAM46C preferentially consumed adenosine triphosphate (ATP) and extended A-rich RNA substrates. FAM46C showed a weaker PAP activity than its homolog FAM46B, and this difference was largely dependent on the residue variance at particular sites. Of them, residues at positions 77, 290, and 298 of mouse FAM46C were most important for the divergence in enzymatic activity. Among the MM-associated FAM46C mutants, those residing at the catalytic site (D90G and D90H) or putative RNA-binding site (I155L, S156F, D182Y, F184L, Y247V, and M270V) showed abolished or compromised PAP activity of FAM46C, while N72A and S248A did not severely affect the PAP activity. FAM46C mutants D90G, D90H, I155L, S156F, F184L, Y247V, and M270V had significantly lower inhibitory effect on apoptosis of RPMI-8226 cells as compared to wild-type FAM46C.
conclusionsFAM46C is a prokaryotic-like PAP with preference for A-rich RNA substrates, and showed distinct enzymatic efficiency with its homolog FAM46B. The MM-related missense mutations of FAM46C lead to various structural and biochemical outcomes to the protein.
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