The non-canonical poly(A) polymerase FAM46C acts as an onco-suppressor in multiple myeloma

Seweryn Mroczek, Justyna Chlebowska, Tomasz M. Kuliński, Olga Gewartowska, Jakub Gruchota, Dominik Cysewski, Vladyslava Liudkovska, Ewa Borsuk, Dominika Nowis and Andrzej Dziembowski ()
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Seweryn Mroczek: University of Warsaw
Justyna Chlebowska: University of Warsaw
Tomasz M. Kuliński: Institute of Biochemistry and Biophysics, Polish Academy of Sciences
Olga Gewartowska: University of Warsaw
Jakub Gruchota: Institute of Biochemistry and Biophysics, Polish Academy of Sciences
Dominik Cysewski: Institute of Biochemistry and Biophysics, Polish Academy of Sciences
Vladyslava Liudkovska: University of Warsaw
Ewa Borsuk: University of Warsaw
Dominika Nowis: University of Warsaw
Andrzej Dziembowski: University of Warsaw

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00578-5

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