Recognizing dUTPase as a mitotic factor essential for early embryonic development

Abstract

dUTPase is universally regarded as a metabolic sanitizing enzyme that protects genomes by preventing the incorporation of uracil into DNA. Despite its essentiality across eukaryotes, no function beyond nucleotide sanitization has been demonstrated. Here, we uncover a conserved, non-canonical role for dUTPase as a regulator of mitosis. Using Drosophila and mouse models, we demonstrate that dUTPase loss causes early embryonic lethality characterized by severe mitotic failure that, cannot be rescued by disabling uracil-DNA repair, uncoupling dUTPase essentiality from DNA repair pathways. Mechanistically, dUTPase dynamically associates with the mitotic spindle and centrosomes, and its depletion induces centrosome amplification and chromosome segregation defects. Beyond cell division, dUTPase dosage bidirectionally controls cell migration, linking its mitotic function to cellular behaviors relevant for metastasis. Together, our findings redefine dUTPase as a moonlighting mitotic factor that coordinates centrosome integrity and spindle dynamics, expanding its known repertoire beyond nucleotide metabolism. HighlightsdUTPase deficiency leads to mitotic defects during early embryonic development in both Drosophila and mouse models dUTPase shows dynamic spatiotemporal localization associated with microtubules through mitosis dUTPase is essential for the normal number and intracellular localization of centrosomes dUTPase deficiency counteracts while its overexpression enhances cell migration