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Synthetic lethality between TP53 and ENDOD1
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Journal Article
Synthetic lethality between TP53 and ENDOD1
2022
Overview
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 H
2
O
2
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.
The authors uncover synthetic lethality between TP53 and ENDOD1, which contains an atypical endonuclease domain. Co-depleted G1 cells accumulate single stranded DNA and die. Combined with xenograft data the work identifies ENDOD1 as a potential cancer-specific SL drug discovery target.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/106
/ 13/31
/ 13/51
/ 14
/ 45
/ 45/22
/ 631/67
/ 631/80
/ 82/29
/ Ablation
/ Animals
/ Cancer
/ DNA
/ Homology
/ Humanities and Social Sciences
/ Humans
/ Mice
/ Nuclease
/ Peptides
/ Science
/ siRNA
/ Synthetic Lethal Mutations - genetics
/ Tumor Suppressor Protein p53 - genetics
/ Tumors
