Cancer-associated SF3B1 mutation suppresses DNA repair by disrupting the organization of nuclear actin network

Nuclear actin filament is required for efficient repair of DNA double-strand breaks. While cancer-associated SF3B1 mutation leads to impaired DNA repair, the underlying mechanism remains elusive. Here, we found that SF3B1 mutation led to defective nuclear actin network during DNA repair. Mechanistically, SF3B1 mutation increased the expression of circATP9B, which interacted with and facilitated the degradation of MYH9. MYH9 deficiency abolished the assembly of nuclear actin network, which, in turn, suppressed the movement and clustering of DNA damage foci, resulting in inefficient DNA repair. Together, our study reveals a novel mechanism by which SF3B1 mutation influences cancer progression via circRNA, and underscores the important role of MYH9 in organization of nuclear actin network.