Synthetic lethality between TP53 and ENDOD1

Zizhi Tang, Ming Zeng, Xiaojun Wang, Chang Guo, Peng Yue, Xiaohu Zhang, Huiqiang Lou, Jun Chen, Dezhi Mu, Daochun Kong, Antony M. Carr () and Cong Liu ()
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Zizhi Tang: West China Second University Hospital, Sichuan University
Ming Zeng: West China Second University Hospital, Sichuan University
Xiaojun Wang: West China Second University Hospital, Sichuan University
Chang Guo: West China Second University Hospital, Sichuan University
Peng Yue: West China Second University Hospital, Sichuan University
Xiaohu Zhang: West China Second University Hospital, Sichuan University
Huiqiang Lou: China Agricultural University
Jun Chen: Zhejiang University
Dezhi Mu: West China Second University Hospital, Sichuan University
Daochun Kong: Peking University
Antony M. Carr: University of Sussex
Cong Liu: West China Second University Hospital, Sichuan University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30311-w

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