Tau condensation on DNA and localization on centromeres: A potential link to cell division

Tau protein, traditionally recognized for stabilizing microtubules and forming pathological aggregates, has recently been observed to form condensates in various contexts. While its condensation with RNA has been well studied, the interaction between tau and DNA, along with its biological significance, remains less explored. Here, using single-molecule experiments, we found that tau binds stably to naked DNA at nanomolar concentrations, leading to the local co- condensation of tau and DNA. These tau condensates on DNA can also interface with microtubules, leveraging tau’s known role in promoting microtubule growth and organization. The dynamic nature of these condensates facilitates the remodeling of the DNA–microtubule assembly. Interestingly, two phosphomimetic tau mutants, T231D/S235D and S262D, retained their affinity for DNA but differed in their ability to link microtubules to DNA. Furthermore, imaging of HEK-293 and SH-SY5Y cells in early mitosis revealed that tau localizes on centromeres, poised to capture nascent mitotic spindles. Building on these observations, we speculate that tau may play a novel role in mitosis, where tau clusters facilitate the early registration of mitotic spindles to chromosomes before kinetochore-mediated attachment. We also discuss the potential implications of this model in conditions where abnormal cell cycle re-entry and tau activity may disrupt cell division.