Drosophila CG3303 is an essential endoribonuclease linked to TDP-43-mediated neurodegeneration

Laneve, Pietro; Piacentini, Lucia; Casale, Assunta Maria; Capauto, Davide; Gioia, Ubaldo; Cappucci, Ugo; Di Carlo, Valerio; Bozzoni, Irene; Di Micco, Patrizio; Morea, Veronica; Di Franco, Carmela Antonia; Caffarelli, Elisa

Based on sequence similarity and domain organization, both CG2145 and DendoU endoribonucleases should be assigned to the Eukaryotic EndoU ribonuclease family. However, deep biochemical characterization revealed distinct features in sequence-specificity and cleavage chemistry. This suggests that they recognize and/or cleave different RNA substrates and act through different catalytic mechanisms in vivo. On this basis, we propose to include only DendoU, which was annotated in databases as putative serine-protease, in the aforementioned family. These findings underline the relevance of combining biochemical and sequence/structure analyses to elucidate protein function. Taking advantage of Drosophila in vivo model system to investigate the contribution of target genes to biological processes, we demonstrated that DendoU is essential for fly viability whereas CG2145 is not. Indeed, DendoU systemic silencing resulted in pupal lethality, indicating that in vivo activity of DendoU is not redundant.