Abstract
FAM46C is one of the most frequently mutated genes in multiple myeloma. Here, using a combination of in vitro and in vivo approaches, we demonstrate that FAM46C encodes an active non-canonical poly(A) polymerase which enhances mRNA stability and gene expression. Reintroduction of active FAM46C into multiple myeloma cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death. Moreover, silencing of FAM46C in multiple myeloma cells expressing WT protein enhance cell proliferation. Finally, using a FAM46C-FLAG knock-in mouse strain, we show that the FAM46C protein is strongly induced during activation of primary splenocytes and that B lymphocytes isolated from newly generated FAM46C KO mice proliferate faster than those isolated from their WT littermates. Concluding, our data clearly indicate that FAM46C works as an onco-suppressor, with the specificity for B-lymphocyte lineage from which multiple myeloma originates.
Highlights
FAM46C is one of the most frequently mutated genes in multiple myeloma
We provide strong in vitro and in culture evidence demonstrating that the FAM46C gene encodes a novel poly(A) polymerase that acts as an B-cell lineage growth suppressor
Reintroduction of FAM46C into MM cell lines with dysfunctional endogenous gene leads to cell death while its silencing in cells expressing WT proteins enhances proliferation rate
Summary
FAM46C is one of the most frequently mutated genes in multiple myeloma. Reintroduction of active FAM46C into multiple myeloma cell lines, but not its catalytically-inactive mutant, leads to broad polyadenylation and stabilization of mRNAs strongly enriched with those encoding endoplasmic reticulum-targeted proteins and induces cell death. We show that FAM46C is an active poly (A) polymerase that positively regulates expression of ER-targeted mRNAs. the presented data strongly indicate that FAM46C is a B-cell lineage-specific growth suppressor as silencing of FAM46C in MM cells that express the wild-type protein enhances cell division, whereas introduction of wild-type FAM46C into MM that express the protein with mutations leads to growth arrest; primary B cells isolated from FAM46C KO animals proliferate faster. We describe FAM46C as an onco-suppressor non-canonical poly(A) polymerase
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