The m6A reader IGF2BP2 promotes homologous recombination-mediated DNA repair by eliminating DNA-RNA hybrids

Abstract

Double-strand breaks (DSBs) are among the most deleterious forms of DNA damage and are precisely repaired through homologous recombination (HR). DNA-RNA hybrids formed at DSB sites play a critical role in HR-mediated repair and must be tightly regulated. Here, we identify the m⁶A reader IGF2BP2, together with the RNA helicase DHX9, as key factors recruited to DSBs that remove DNA-RNA hybrids in an m⁶A-dependent manner. This axis prevents hybrid accumulation, enables RAD51 loading, and promotes HR-mediated repair. Loss of IGF2BP2 sensitizes cancer cells and xenograft tumors to DNA damage-inducing therapies, revealing therapeutic implications.