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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 (517-1,093), 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 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.

Original publication

DOI

10.26508/lsa.202000795

Type

Journal article

Journal

Life science alliance

Publication Date

01/2021

Volume

4

Addresses

Structural Genomics Consortium, University of Oxford, Oxford, UK.

Keywords

HCT116 Cells, Humans, Colorectal Neoplasms, DNA Damage, Zinc, Cell Cycle Proteins, Proto-Oncogene Proteins, DNA, Adenosine Diphosphate, Adenosine Triphosphate, Crystallization, Magnetic Resonance Spectroscopy, Transfection, Cell Survival, Gene Silencing, Catalytic Domain, Hydrolysis, Models, Molecular, Microsatellite Instability, Werner Syndrome Helicase, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Serine-Threonine Kinases