Cytoplasmic polyadenylation by TENT5A is required for proper bone formation

Cell Rep. 2021 Apr 20;35(3):109015. doi: 10.1016/j.celrep.2021.109015.

Olga Gewartowska ¹, Goretti Aranaz-Novaliches ², Paweł S Krawczyk ³, Seweryn Mroczek ⁴, Monika Kusio-Kobiałka ¹, Bartosz Tarkowski ³, Frantisek Spoutil ⁵, Oldrich Benada ⁶, Olga Kofroňová ⁶, Piotr Szwedziak ⁷, Dominik Cysewski ⁸, Jakub Gruchota ³, Marcin Szpila ³, Aleksander Chlebowski ⁸, Radislav Sedlacek ⁵, Jan Prochazka ⁵, Andrzej Dziembowski ⁹

Affiliations

1 Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland.
2 Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
3 Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.
4 Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland.
5 Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic; Czech Centre for Phenogenomics, Institute of Molecular Genetics of the CAS, Prague, Czech Republic.
6 Institute of Microbiology of the Czech Academy of Sciences, v.v.i., 142 20 Prague 4, Czech Republic.
7 Laboratory of Structural Cell Biology, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland; ReMedy-International Research Agenda Unit, Centre of New Technologies, University of Warsaw, 02-097 Warsaw, Poland.
8 Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland.
9 Laboratory of RNA Biology, International Institute of Molecular and Cell Biology in Warsaw, Trojdena 4, 02-109 Warsaw, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland. Electronic address: adziembowski@iimcb.gov.pl.

PMID: 33882302 DOI: 10.1016/j.celrep.2021.109015

Abstract

Osteoblasts orchestrate bone formation through the secretion of type I collagen and other constituents of the matrix on which hydroxyapatite crystals mineralize. Here, we show that TENT5A, whose mutations were found in congenital bone disease osteogenesis imperfecta patients, is a cytoplasmic poly(A) polymerase playing a crucial role in regulating bone mineralization. Direct RNA Sequencing revealed that TENT5A is induced during osteoblast differentiation and polyadenylates mRNAs encoding Col1α1, Col1α2, and other secreted proteins involved in osteogenesis, increasing their expression. We postulate that TENT5A, possibly together with its paralog TENT5C, is responsible for the wave of cytoplasmic polyadenylation of mRNAs encoding secreted proteins occurring during bone mineralization. Importantly, the Tent5a knockout (KO) mouse line displays bone fragility and skeletal hypomineralization phenotype resulting from quantitative and qualitative collagen defects. Thus, we report a biologically relevant posttranscriptional regulator of collagen production and, more generally, bone formation.

Keywords

FAM46A; Nanopore; TENT5A; collagen; direct RNA sequencing; osteoblasts; osteogenesis; osteogenesis imperfecta; poly(A) tail; polyadenylation.

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