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Synthetic lethality between TP53 and ENDOD1.

Zizhi Tang1, Ming Zeng1, Xiaojun Wang1

  • 1Department 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.

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|May 23, 2022
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Summary
This summary is machine-generated.

The DNA repair enzyme ENDOD1 has a novel role in preventing DNA damage. Loss of ENDOD1 causes synthetic lethality with TP53 mutations, offering a potential new cancer therapy target.

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Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • The atypical nuclease ENDOD1 is known for its role in innate immunity with cGAS-STING.
  • A previously uncharacterized function of ENDOD1 in DNA repair is investigated.

Purpose of the Study:

  • To elucidate the novel DNA repair functions of ENDOD1.
  • To explore the potential of ENDOD1 as a synthetic lethal target in cancer therapy, particularly in tumors with TP53 mutations.

Main Methods:

  • Investigated ENDOD1 localization in response to H2O2-induced DNA damage.
  • Analyzed PARP chromatin association in ENDOD1 knockout cells.
  • Assessed synthetic lethality between ENDOD1 loss and homologous recombination or p53 defects.
  • Utilized in vivo xenograft models with whole-animal siRNA for ENDOD1 to evaluate tumor growth inhibition.

Main Results:

  • ENDOD1 is enriched in the nucleus after H2O2 treatment, indicating a role in DNA repair.
  • ENDOD1 deficiency leads to synthetic lethality with homologous recombination defects, causing DNA double-strand breaks.
  • A synthetic lethal interaction was discovered between ENDOD1 and p53, where ENDOD1 depletion in TP53-mutated cells or p53 depletion in ENDOD1-deficient cells causes single-stranded DNA accumulation and cell death.
  • Systemic knockdown of mouse EndoD1 was well-tolerated, and human ENDOD1 siRNA restrained tumor progression in xenografts with TP53 mutations.

Conclusions:

  • ENDOD1 plays a critical role in DNA repair and maintains genomic stability.
  • The synthetic lethality between ENDOD1 and p53 highlights ENDOD1 as a promising, wide-spectrum target for synthetic lethal cancer therapies, especially for the ~50% of tumors with TP53 mutations.
  • ENDOD1 targeting demonstrates potential for cancer-specific drug discovery and therapeutic intervention.