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Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer

ABSTRACT: Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer

PROVIDER: PRJNA893644 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22030035_1.fastq.gz	Fastqsanger.gz
	SRR22030035_2.fastq.gz	Fastqsanger.gz
	SRR22030036_1.fastq.gz	Fastqsanger.gz
	SRR22030036_2.fastq.gz	Fastqsanger.gz
	SRR22030037_1.fastq.gz	Fastqsanger.gz

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Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer

Project description:Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype p53 knock-in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA_x0002_dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts (PDX). Interestingly, p53 gene remains wildtype in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-wildtype MSI CRCs.

2022-10-26 | GSE216455 | GEO

Synthetical lethality of Werner helicase and mismatch repair deficiency is mediated by p53 and PUMA in colon cancer.

Project description:Synthetic lethality is a powerful approach for targeting oncogenic drivers in cancer. Recent studies revealed that cancer cells with microsatellite instability (MSI) require Werner (WRN) helicase for survival; however, the underlying mechanism remains unclear. In this study, we found that WRN depletion strongly induced p53 and its downstream apoptotic target PUMA in MSI colorectal cancer (CRC) cells. p53 or PUMA deletion abolished apoptosis induced by WRN depletion in MSI CRC cells. Importantly, correction of MSI abrogated the activation of p53/PUMA and cell killing, while induction of MSI led to sensitivity in isogenic CRC cells. Rare p53-mutant MSI CRC cells are resistant to WRN depletion due to lack of PUMA induction, which could be restored by wildtype (WT) p53 knock in or reconstitution. WRN depletion or treatment with the RecQ helicase inhibitor ML216 suppressed in vitro and in vivo growth of MSI CRCs in a p53/PUMA-dependent manner. ML216 treatment was efficacious in MSI CRC patient-derived xenografts. Interestingly, p53 gene remains WT in the majority of MSI CRCs. These results indicate a critical role of p53/PUMA-mediated apoptosis in the vulnerability of MSI CRCs to WRN loss, and support WRN as a promising therapeutic target in p53-WT MSI CRCs.

| S-EPMC9907101 | biostudies-literature

H2O2 effect on mouse embryonic fibroblasts +/- a deletion in the helicase domain of the Werner Syndrome gene homologue

Project description:[original Title] Expression profiling of mouse embryonic fibroblasts with or without a deletion in the helicase domain of the Werner Syndrome gene homologue treated with hydrogen peroxide Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. In addition to genomic instability, WS cells exhibit oxidative stress. In this report, we have examined the impact of exogenous peroxide on the expression profile of mouse embryonic fibroblasts lacking part of the helicase domain of the WRN homologue. This expression profile was compared to hydrogen peroxide treated wild type mouse embryonic fibroblasts. Interestingly, untreated mouse embryonic fibroblasts with a deletion of the helicase domain of Wrn already exhibited down regulation of several biological processes decreased by hydrogen peroxide in wild type cells.

2009-11-13 | GSE19007 | GEO

Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability

Project description:Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability

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Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability [PacBio]

Project description:Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability [PacBio]

| PRJNA645165 | ENA

Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability (WGS)

Project description:Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability (WGS)

| PRJNA629786 | ENA

Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability (END-Seq)

Project description:Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability (END-Seq)