The atypical nuclease ENDOD1 functions with cGAS-STING in innate immunity. Here we identify a previously uncharacterized ENDOD1 function in DNA repair. ENDOD1 is enriched in the nucleus following H₂O₂ treatment and ENDOD1^-/- cells show increased PARP chromatin-association. Loss of ENDOD1 function is synthetic lethal with homologous recombination defects, with affected cells accumulating DNA double strand breaks. Remarkably, we also uncover an additional synthetic lethality between ENDOD1 and p53. ENDOD1 depletion in TP53 mutated tumour cells, or p53 depletion in ENDOD1^-/- cells, results in rapid single stranded DNA accumulation and cell death. Because TP53 is mutated in ∼50% of tumours, ENDOD1 has potential as a wide-spectrum target for synthetic lethal treatments. To support this we demonstrate that systemic knockdown of mouse EndoD1 is well tolerated and whole-animal siRNA against human ENDOD1 restrains TP53 mutated tumour progression in xenograft models. These data identify ENDOD1 as a potential cancer-specific target for SL drug discovery.

中文翻译：

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TP53 和 ENDOD1 之间的合成杀伤力

非典型核酸酶 ENDOD1 在先天免疫中与 cGAS-STING 一起发挥作用。在这里，我们确定了 DNA 修复中以前未表征的 ENDOD1 功能。H ₂ O ₂处理后， ENDOD1 在细胞核中富集， ENDOD1 ^-/-细胞显示 PARP 染色质结合增加。ENDOD1 功能的丧失是合成致死的，具有同源重组缺陷，受影响的细胞积累 DNA 双链断裂。值得注意的是，我们还发现了 ENDOD1 和 p53 之间的额外合成杀伤力。TP53突变肿瘤细胞中的ENDOD1 消耗，或ENDOD1 ^-/-细胞中的 p53 消耗，导致快速单链 DNA 积累和细胞死亡。因为TP53在约 50% 的肿瘤中发生突变，ENDOD1 具有作为合成致死治疗的广谱靶点的潜力。为了支持这一点，我们证明了小鼠EndoD1的系统性敲低具有良好的耐受性，并且针对人ENDOD1的全动物 siRNA在异种移植模型中抑制了TP53突变的肿瘤进展。这些数据将 ENDOD1 确定为 SL 药物发现的潜在癌症特异性靶标。