s41467-022-30311-w.pdf (2.37 MB)
Synthetic lethality between TP53 and ENDOD1
journal contribution
posted on 2023-06-10, 05:28 authored by Zishi Tang, Ming Zeng, Xiaojun Wang, Chang Guo, Peng Yue, Xiaohu Zhang, Huiqiang Lou, Jun Chen, Dezhi Mu, Daochun Kong, Antony CarrAntony Carr, Cong LiuCong LiuThe 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.
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Publication status
- Published
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- Published version
Journal
Nature CommunicationsISSN
2041-1723Publisher
Springer Science and Business Media LLCExternal DOI
Volume
13Page range
a2861 1-12Event location
EnglandDepartment affiliated with
- Sussex Centre for Genome Damage Stability Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-11-15First Open Access (FOA) Date
2022-11-15First Compliant Deposit (FCD) Date
2022-11-15Usage metrics
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