Synthetic lethality between TP53 and ENDOD1
| Autor: | 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 |
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| Rok vydání: | 2021 |
| Předmět: |
Drug
DNA Repair Poly ADP ribose polymerase media_common.quotation_subject General Physics and Astronomy Synthetic lethality General Biochemistry Genetics and Molecular Biology chemistry.chemical_compound Endonuclease Mice Neoplasms Cytotoxic T cell Animals Humans Cytotoxicity media_common Multidisciplinary biology General Chemistry Hydrogen Peroxide chemistry Cancer research biology.protein Tumor Suppressor Protein p53 Homologous recombination Synthetic Lethal Mutations DNA |
| Zdroj: | Nature communications. 13(1) |
| ISSN: | 2041-1723 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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