Tau condensation on DNA mediates microtubule attachment suggesting a mitotic role for centromere-localized tau

Abstract

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 find 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, phosphorylated tau and nucleosomal DNA exhibit distinct capacities to form condensates and recruit microtubules. Furthermore, imaging of mitotic cells with endogenous or exogenous tau reveals its localization to centromeres, engaging mitotic spindles, whereas expression of phosphomimetic tau mutants (T231D/S235D and S262D) causes defects in chromosome alignment. Building on these observations, we speculate that tau may play a role in mitosis, where tau clusters facilitate the early registration of mitotic spindles to chromosomes before kinetochore-mediated attachment. We also discuss the implications of this model in conditions where abnormal cell cycle re-entry and tau activity may disrupt cell division.