The mechanism of posttranscriptional modification of messenger RNA encoding collagen, which dysfunction leads to congenital bone fragility, is described in the latest Cell Reports issue. The authors are scientists from the Laboratory of RNA Biology of IIMCB together with collaborators from research centers in Poland and the Czech Republic.
Collagen is the most abundant protein in the human body, making up about 30% of all proteins. There are several types of this structural protein, and abnormalities in the synthesis of collagen manifest in various diseases affecting, among others, bones, skin, muscles, and blood vessels.
Type I collagen is found primarily in bones, tendons, and skin. Mutations in genes coding collagen or proteins involved in its synthesis lead to a rare but very serious bone disease - Osteogenesis imperfecta. The bones of patients suffering from this disease are very susceptible to fractures, which occur after minimal trauma or, even without trauma, in the most severe cases. Congenital bone fragility is incurable, and only symptomatic treatment is used, which in some patients can reduce the frequency of fractures.
Collagen synthesis is a very complex process involving a number of accessory proteins. When the process works properly, long, very mechanically resistant collagen fibers are formed. Most patients with congenital bone fragility have a mutation in the genes that encode collagen chains - Col1a1 or Col1a2. These mutations cause collagen not to be produced in sufficient quantity or to be of poor quality. In recent years, a number of mutations have been identified in genes encoding proteins necessary for collagen synthesis that also cause various forms of congenital bone fragility. One of these genes is Tent5a, which product belongs to the family of enzymes that add poly(A) tails to the cytoplasm. It is the focus of Professor Andrzej Dziembowski's laboratory.
In the presented work, using mouse models, modern imaging, and molecular biology techniques, the authors have demonstrated that the activity of the TENT5A protein is essential for normal bone formation. TENT5A is expressed in bone-forming cells - osteoblasts and their mature form - osteocytes. This enzyme acts in the cytoplasm and elongates the poly(A) tails of mRNAs encoding collagen and Sparc and SerpinF1, involved in downstream steps of collagen synthesis. In this case, if the poly(A) mRNA tails are not elongated, the levels of the proteins they encode are very low. As a consequence, too small amounts of collagen are produced in and the quality is also poor: the fibers are thinner than they should be and easily degraded. At the level of the body, this results in brittle and fragile bones.
In conclusion: the pathomechanism of the development of congenital bone disease has been described, which will allow a better molecular diagnosis of the patients. In the future, it may enable the development of new therapeutic approaches.
Olga Gewartowska, Goretti Aranaz Novaliches, Paweł S. Krawczyk, Seweryn Mroczek, Monika Kusio-Kobiałka, Bartosz Tarkowski, Frantisek Spoutil, Oldrich Benada, Olga Kofroňová, Piotr Szwedziak, Dominik Cysewski, Jakub Gruchota, Marcin Szpila, Aleksander Chlebowski, Radislav Sedlacek, Jan Prochazka, Andrzej Dziembowski. Cytoplasmic polyadenylation by TENT5A is required for proper bone formation. Cell Reports, 2021; doi: 10.1016/j.celrep.2021.109015