由IR诱导的DSB的修复主要是通过非同源末端连接（NHEJ）途径进行的，而53BP1在其中发挥关键作用。我们发现EMT诱导的转录抑制因子ZEB1（i）与53BP1相互作用，并且在细胞暴露于IR后，这种相互作用迅速发生并显著增强；（ii）对于53BP1在某些双链断裂位点的定位和生理DSB修复是必需的；（iii）与53BP1在IR诱导的聚焦点（IRIF）共定位；（iv）促进NHEJ并抑制同源重组（HR）；（v）缺乏导致DSB的重切，（vi）在BRCA1缺陷细胞上使其对PARP抑制剂（PARPi）敏感。最后，ZEB1对修复途径选择、重切和PARPi敏感性的影响都依赖于其homeodomain。与高表达ZEB1的癌细胞经充分研究的治疗抵抗相反，这里描述的新型ZEB1-53BP1-shieldin重切轴显示出治疗上的易感性：BRCA1缺陷肿瘤中ZEB1水平可能作为对PARPi反应的预测生物标记。© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.

Repair of DSB induced by IR is primarily carried out by Non-Homologous End Joining (NHEJ), a pathway in which 53BP1 plays a key role. We have discovered that the EMT-inducing transcriptional repressor ZEB1 (i) interacts with 53BP1 and that this interaction occurs rapidly and is significantly amplified following exposure of cells to IR; (ii) is required for the localization of 53BP1 to a subset of double-stranded breaks, and for physiological DSB repair; (iii) co-localizes with 53BP1 at IR-induced foci (IRIF); (iv) promotes NHEJ and inhibits Homologous Recombination (HR); (v) depletion increases resection at DSBs and (vi) confers PARP inhibitor (PARPi) sensitivity on BRCA1-deficient cells. Lastly, ZEB1's effects on repair pathway choice, resection, and PARPi sensitivity all rely on its homeodomain. In contrast to the well-characterized therapeutic resistance of high ZEB1-expressing cancer cells, the novel ZEB1-53BP1-shieldin resection axis described here exposes a therapeutic vulnerability: ZEB1 levels in BRCA1-deficient tumors may serve as a predictive biomarker of response to PARPis.© The Author(s) 2023. Published by Oxford University Press on behalf of Nucleic Acids Research.