m7G modification in mRNA cooperates with QKI to promote homologous recombination repair.

Abstract

DNA double strand breaks (DSBs) are repaired through distinct pathways, with homologous recombination (HR) favored when DNA ends undergo extensive resection. Although cytoplasmic N7-methylguanosine (m7G)-modified RNA increases after UV-induced single-strand breaks, its role in DSB repair (including HR) remains unclear. Here, we show that m7G-modified RNA accumulates at DSB sites, where it recruits the m7G reader protein Quaking (QKI)5, to selectively promote HR. Mechanistically, QKI5 directly interacts with MRE11 and enhances its DNA binding affinity, thereby facilitating DNA end resection. Depletion of QKI5 impairs recruitment of the MRE11-RAD50-NBS1 complex to DSBs and reduces HR repair efficiency. Moreover, elevated QKI5 expression is associated with resistance to radiotherapy in both mouse models and clinical cohorts. Together, these findings identify the m7G RNA-QKI5-MRE11 axis as a regulator of HR pathway choice and suggest QKI5 as a promising therapeutic target in cancer treatment.