Synthetic lethality between TP53 and ENDOD1

Abstract

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.

Systematic analysis of cancer‐specific synthetic lethal interactions provides insight into personalized anticancer therapy

“…Of these, TP53 and TTN were detected with higher rates than other genes. Indeed, TP53 mutations were associated with multiple cancers as a potential therapeutic target [33–35], and synthetic lethality between TP53 and ENDOD1 implicated ENDOD1 as a potential cancer‐specific target for drug discovery [36]. Many of these 45 genes were involved in multiple interactions with other genes (median value = 72) (Fig.…”

Mechanistic basis for targeting homologous recombination defective liver cancer via synthetic lethality

“…This underlines the potential for SL treatment using PARPi. In previous work we identified the atypical nuclease ENDOD1 as a protein required in human cells to reduce the levels of trapped PARP and showed that ENDOD1 ablated cells were synthetic lethal with homologous recombination defects 26 . Here we show knockdown of ENDOD1 causes increased levels of DNA damage and forces cytotoxicity in the context of HBx expression and, using xenografts, show that knockdown of ENDOD1 by whole animal siRNA results in reduced tumour growth.…”

“…We recently uncovered an atypical endonuclease (ENDOD1) that counteracts PARP trapping on damaged chromatin 26 and demonstrated cell lethality upon concomitant ENDOD1-HR ablation. This potentially establishes a second therapeutic SL pair other than PARPi-HRD.…”

“…To establish if the consequent HRD can be exploited to treat HBV positive cancer, we examined the impact on tumour-promotion of in vivo ablation of murine Wdr70 with Trp53 positive and negative backgrounds and demonstrate Wdr70 knockdown synergises with p53 -/- to promote tumorigenesis. Finally, we use cell and patient derived xenograft models to demonstrate that PARP inhibition or systemic knockdown of ENDOD1 , an atypical nuclease recently shown to be synthetic lethal with HRD 26 , restrained tumour growth. Our data conceptualize SL regimes for HBVHCC based on sensitivity to HRD-targeting therapy.…”

The biological essence of synthetic lethality: Bringing new opportunities for cancer therapy

“…Consistently, siRNA against human ENDOD1 significantly inhibited the growth of TP53‐mutated xenograft tumors in EndoD1‐systemic knockdown mice. Therefore, ENDOD1 is an attractive synthetic lethal target for TP53 mutated cancers, which accounts for approximately 50% of cancers 72 . CHK1 is a crucial replication stress checkpoint kinase that maintains genome stability by controlling the cell cycle in response to DNA damage 73,74 .…”