Abstract

The spatial distribution and dynamics of double-strand break (DSBs) repair controlled by microtubules are essential for preserving genomic stability. However, the processes through which extranuclear microtubules govern intranuclear DSB repair across the nuclear envelope (NE) remain poorly understood. This study uncovers a mechanism by which the microtubule-depolymerizing kinesin KIF2A regulates nonhomologous end joining (NHEJ) repair by mediating NE invagination. Our investigation reveals that damage-induced α-tubulin tyrosination triggers KIF2A binding to microtubules, subsequently inducing NE invagination through the microtubule-the linker of nucleoskeleton and cytoskeleton (LINC) complex and lamin B1. This invagination, in turn, provides a larger region of a stable NHEJ repair environment close to the NE, facilitating efficient NHEJ repair. Loss of KIF2A disrupts the formation of invaginations after DNA damage, impacting the formation of 53BP1 foci. Our study establishes KIF2A-mediated NE invagination as a critical regulator of the intricate relationships among microtubules, NE dynamics, and NHEJ repair, shedding light on a previously obscure pathway crucial for genome stability.