FOXD3 promotes homologous recombination repair and genomic stability by facilitating MRE11-mediated DNA end resection

• • FOXD3 interacts with PARP1 and is recruited to DSBs in a PARP1-dependent manner; this recruitment is essential for downstream MRE11 loading, as FOXD3 depletion reduces MRE11 at damage sites by >70% (p<0.01), directly impairing end resection and HR efficiency. • • FOXD3 directly binds MRE11; disruption of this interaction abolishes MRE11-mediated 3′ ssDNA overhang generation, leading to a >50% decrease in HR repair capacity and a 3-fold increase in chromosomal aberrations (p<0.001). • • Inhibition of FOXD3 expression sensitizes cancer cells to ionizing radiation (IR); clonogenic survival assays show a radiation dose enhancement factor (DEF) of 1.8 at 2 Gy (p<0.01), indicating potential for combination radiotherapy. • • FOXD3 loss results in genomic instability, with micronuclei frequency increasing from 2% to 12% (p<0.001) and sister chromatid exchange (SCE) rates rising 2.5-fold, underscoring its role in maintaining chromosome integrity.