Synthetic lethality between TP53 and ENDOD1

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.