Synthetic Lethality Between TP53 and ENDOD1

Overview

Journal Nat Commun

Specialty Biology

Date 2022 May 23

PMID 35606358

Authors

Zizhi Tang

Ming Zeng

Xiaojun Wang

Chang Guo

Peng Yue

Xiaohu Zhang

Huiqiang Lou

Jun Chen

Dezhi Mu

Daochun Kong

Antony M Carr

Cong Liu

Affiliations

Soon will be listed here.

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 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.

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