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

Nat Commun. 2017 Sep 20;8(1):619. doi: 10.1038/s41467-017-00578-5.

Seweryn Mroczek ¹ ², Justyna Chlebowska ¹ ³ ⁴ ⁵, Tomasz M Kuliński ², Olga Gewartowska ¹ ², Jakub Gruchota ² ⁶, Dominik Cysewski ², Vladyslava Liudkovska ¹, Ewa Borsuk ⁷, Dominika Nowis ⁴ ⁵, Andrzej Dziembowski ⁸ ⁹

Affiliations

1 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106, Warsaw, Poland.
2 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warsaw, Poland.
3 Department of Immunology, Center of Biostructure Research, Medical University of Warsaw, Banacha 1a, 02-097, Warsaw, Poland.
4 Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw, Banacha 2c, 02-097, Warsaw, Poland.
5 Genomic Medicine, Medical University of Warsaw, Banacha 1a, 02-097, Warsaw, Poland.
6 International Institute of Molecular and Cell Biology, Trojdena 4, 02-109, Warsaw, Poland.
7 Department of Embryology, Institute of Zoology, Faculty of Biology, University of Warsaw, Miecznikowa 1, 02-096, Warsaw, Poland.
8 Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106, Warsaw, Poland. andrzejd@ibb.waw.pl.
9 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warsaw, Poland. andrzejd@ibb.waw.pl.

PMID: 28931820 DOI: 10.1038/s41467-017-00578-5

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. FAM46C is one of the most frequently mutated genes in multiple myeloma (MM), but its molecular function remains unknown. Here the authors show that FAM46C is a poly(A) polymerase and that loss of function of FAM46C drives multiple myeloma through the destabilisation of ER response transcripts.

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