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.

Czech Centre for Phenogenomics Institute of Molecular Genetics of the CAS Prague Czech Republic

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

Institute of Microbiology of the Czech Academy of Sciences v v i 142 20 Prague 4 Czech Republic

Laboratory of RNA Biology International Institute of Molecular and Cell Biology in Warsaw Trojdena 4 02 109 Warsaw Poland

Laboratory of Structural Cell Biology Centre of New Technologies University of Warsaw 02 097 Warsaw Poland

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

ReMedy International Research Agenda Unit Centre of New Technologies University of Warsaw 02 097 Warsaw Poland

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$a Cytoplasmic polyadenylation by TENT5A is required for proper bone formation / $c O. Gewartowska, G. Aranaz-Novaliches, PS. Krawczyk, S. Mroczek, M. Kusio-Kobiałka, B. Tarkowski, F. Spoutil, O. Benada, O. Kofroňová, P. Szwedziak, D. Cysewski, J. Gruchota, M. Szpila, A. Chlebowski, R. Sedlacek, J. Prochazka, A. Dziembowski

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$a 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.

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