Nup98 regulates the G1/S transition

Nuclear pore complexes (NPCs) are embedded throughout the nuclear envelope of all eukaryotic cells and are composed of 30 unique proteins called nucleoporins (Nups). While Nups primarily function at NPCs, multiple Nups function in the nucleoplasm independent of the NPC. We previously found that Nup98-96 is necessary for entry into S phase in Drosophila cells, however, the mechanism is unknown. Here, we demonstrate that Nup98-96 is one of only a subset of Nup genes that can promote entry into S phase. We identify that transcripts dependent on Nup98-96 in Drosophila cells are enriched in cell cycle processes and that many of these transcripts are also dependent on the cell cycle regulator, E2f1. Importantly, we find that entry into S phase can be rescued by co-depleting the CycE/CDK2 inhibitor, dacapo, in Nup98-96-depleted cells. Furthermore, Nup96-98 promotes S phase entry across multiple cell and tissue types and cell cycle contexts. Critically, overexpression of Nup98 has a dominant-negative effect on entry into S phase in larval salivary glands, suggesting that Nup98, not Nup96, promotes entry into S phase. Our work identifies Nup98 as a key regulator of the G1/S transition in metazoans.