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Background  Multiple 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.    Methods  We 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.    Results  We 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.    Conclusions  FAM46C 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.

Structural and functional characterization of multiple myeloma associated cytoplasmic poly(A) polymerase FAM46C