Department of Paediatrics, SCU-CUHK Joint Laboratory for Reproductive Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Ministry of Education), West China Second University Hospital, Sichuan University, 610041, Chengdu, China.
School of Life Sciences, China Agricultural University, 100193, Beijing, China.
Nat Commun. 2022 May 23;13(1):2861. doi: 10.1038/s41467-022-30311-w.
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 HO 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.
非典型核酸内切酶 ENDOD1 与 cGAS-STING 在先天免疫中协同作用。在此，我们发现了 ENDOD1 在 DNA 修复中的一个先前未被描述的功能。HO 处理后，ENDOD1 在内核中富集，并且 ENDOD1 细胞显示出 PARP 染色质结合增加。缺失 ENDOD1 功能与同源重组缺陷具有合成致死性，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 之间的另一种合成致死性。TP53 突变肿瘤细胞中 ENDOD1 的缺失，或 ENDOD1 细胞中 p53 的缺失，导致单链 DNA 迅速积累和细胞死亡。因为 TP53 在约 50%的肿瘤中发生突变，所以 ENDOD1 有可能成为广谱合成致死治疗的靶点。为了支持这一点，我们证明了系统敲低小鼠 EndoD1 是可以耐受的，并且针对人 ENDOD1 的全动物 siRNA 可以抑制异种移植模型中 TP53 突变肿瘤的进展。这些数据表明 ENDOD1 是一种潜在的癌症特异性 SL 药物发现靶标。
