Regulation of Microtubule Stability by a Histone Methyltransferase Subunit

Microtubules are dynamic protein polymers that form the cellular cytoskeleton. Their dynamics play a crucial role in proper cell division, among many other important functions. On the other hand, WD repeat-containing protein 5 (WDR5) is a regulatory subunit of histone H3 lysine 4 methyltransferase complexes (H3K4MTs), a complex that serves in epigenetic regulation by methylating histone H3 at lysine 4. WDR5 has roles in the process of abscission, whereas abscission requires the depolymerization of microtubules. Knocking down WDR5 increases midbody microtubule stability. Kinesin heavy chain member 2A (KIF2A), a microtubule depolymerizing enzyme, has been found to localize to midbody microtubules and interact with WDR5. This project aims to test whether KIF2A is the link between midbody microtubule stability and WDR5. The results of an in vitro microtubule assay suggest that WDR5 binds directly to KIF2A and inhibits its ability to depolymerize microtubules. However, this conflicts with the increase in midbody microtubule stability when WDR5 is knocked down. Future investigations will examine whether WDR5 is able to interact with proteins which are closely related with KIF2A. If so, these interactions could help reconcile our in vivo and in vitro observations. Another future aim is to test whether a WDR5 homolog, WDR5B, is also involved in regulating midbody microtubule stability. These efforts will reveal unconventional functions and roles of H3K4MT subunits in regulating microtubules. Since both H3K4MTs and microtubules are tightly linked to several basic cellular functions and diseases, this insight can have broad impact and valuable applications to many biomedical fields.