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Synthetic lethality between TP53 and ENDOD1

Author

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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
    University of Sussex)

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.

Suggested Citation

  • 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, 2022. "Synthetic lethality between TP53 and ENDOD1," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30311-w
    DOI: 10.1038/s41467-022-30311-w
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    1. Hannah Farmer & Nuala McCabe & Christopher J. Lord & Andrew N. J. Tutt & Damian A. Johnson & Tobias B. Richardson & Manuela Santarosa & Krystyna J. Dillon & Ian Hickson & Charlotte Knights & Niall M. , 2005. "Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy," Nature, Nature, vol. 434(7035), pages 917-921, April.
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