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

ABSTRACT: Our study uncovers a distinct biomarker for MSI that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics

ORGANISM(S): Homo sapiens

PROVIDER: GSE149708 | GEO | 2020/10/01

REPOSITORIES: GEO

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

Project description:Our study uncovers a distinct biomarker for MSI that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics

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

Project description:Our study uncovers a distinct biomarker for MSI that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics

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

Project description:Our study uncovers a distinct biomarker for MSI that underlies the synthetic lethal dependence on WRN, thereby supporting the development of WRN-based therapeutics

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Structure of the helicase core of Werner Helicase, a key target in microsatellite instability cancers

Project description:Loss of WRN, a DNA repair helicase, was identified as a strong vulnerability of microsatellite instable(MSI) cancers, making WRN a promising drug target. We show that ATP binding and hydrolysis are required for genome integrity and viability of MSI cancer cells. We report a 2.2 Å crystal structure of the WRN helicase core (517-1093), comprising the two helicase subdomains and winged helix domain but not the HRDC domain or nuclease domains. The structure highlights unusual features: First, an atypical mode of nucleotide binding that results in unusual relative positioning of the two helicase subdomains. Second, an additional β-hairpin in the second helicase subdomain and an unusual helical hairpin in the Zn2+ binding domain. Modelling of the WRN helicase in complex with DNA suggests roles for these features in the binding of alternative DNA structures. NMR analysis of shows a weak interaction between the HRDC domain and the helicase core, indicating a possible biological role for this association. Together, this study will facilitate the structure-based development of inhibitors against WRN helicase.

2020-11-11 | PXD018910 | Pride

Werner Helicase Prevents Cell Death in Cancers with Microsatellite Instability

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-10-01 | GSE149709 | 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 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.

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

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

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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]

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

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