Both DNA binding domains of p53 are required for its ultra-rapid recruitment to sites of UV damage

Wang, YH; Ho, Teck-Hua; Hariharan, Anushya; Goh, Hc.; Mp, Sheetz; Dp, Lane

doi:10.1101/2020.02.09.938993

Cited by 2 publications

(1 citation statement)

References 14 publications

(17 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TP53 mutations in human cancers exhibit diverse functional consequences including loss- and gain-of-function 17 and almost invariably display abnormal DNA binding and transcriptional properties 18 . A recent study reported rapid PARP-dependent recruitment of p53 to sites of DNA damage that required the DNA binding and carboxyl terminal domains of p53 19 . We therefore assayed the production of pRPA32 foci upon si ENDOD1 in a range of cell lines with defined TP53 mutations.…”

Section: Resultsmentioning

confidence: 99%

Synthetic lethality between TP53 and ENDOD1

Tang

Zeng

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Conventional cytotoxic cancer therapy is limited by adverse side-effects on non-affected tissues. Conversely, synthetic lethal anti-cancer approaches have the potential to reduce systemic cytotoxicity, but most potential synthetic lethality targets are not wide-spectrum and thus the subtype-specific drug targets each have limited application. We identified endonuclease D1 (ENDOD1) in a proteomic characterization of the biological response of PARP inhibition and show that ENDOD1 is recruited to PAR-positive single strand breaks, where it influences the kinetics of single-strand break repair. As with PARPi, ENDOD1 depletion triggered DNA double strand breaks in cycling cells when homologous recombination repair was defective. However, unlike PARPi, ENDOD1 depletion prompted the generation of tracts of single strand DNA in both cycling and G1 arrested p53 defective cells. This identifies a new synthetic lethal interaction that we show encompasses the majority of TP53 hotspot mutations. We conclude that ENDOD1 is a promising wide-spectrum anti-cancer drug target.

show abstract

Section: Resultsmentioning

confidence: 99%

Synthetic lethality between TP53 and ENDOD1

Tang

Zeng

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

Synthetic lethality between TP53 and ENDOD1

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Both DNA binding domains of p53 are required for its ultra-rapid recruitment to sites of UV damage

Cited by 2 publications

References 14 publications

Synthetic lethality between TP53 and ENDOD1

Synthetic lethality between TP53 and ENDOD1

Synthetic lethality between TP53 and ENDOD1

Contact Info

Product

Resources

About