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Werner Syndrome Helicase Is Required for the Survival of Cancer Cells with Microsatellite Instability.

ABSTRACT: Werner syndrome protein (WRN) is a RecQ enzyme involved in the maintenance of genome integrity. Germline loss-of-function mutations in WRN led to premature aging and predisposition to cancer. We evaluated synthetic lethal (SL) interactions between WRN and another human RecQ helicase, BLM, with DNA damage response genes in cancer cell lines. We found that WRN was SL with a DNA mismatch repair protein MutL homolog 1, loss of which is associated with high microsatellite instability (MSI-H). MSI-H cells exhibited increased double-stranded DNA breaks, altered cell cycles, and decreased viability in response to WRN knockdown, in contrast to microsatellite stable (MSS) lines, which tolerated depletion of WRN. Although WRN is the only human RecQ enzyme with a distinct exonuclease domain, only loss of helicase activity drives the MSI SL interaction. This SL interaction in MSI cancer cells positions WRN as a relevant therapeutic target in patients with MSI-H tumors.

SUBMITTER: Kategaya L

PROVIDER: S-EPMC6441948 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells.

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

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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.

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