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Unravelling WRN helicase: Structural Insights Reveal Conformational States and Opportunities for MSI-H Cancer Drug Discovery

ABSTRACT: Werner syndrome helicase (WRN) is a RecQ-family DNA helicase essential for genome maintenance and is a synthetic lethal target in microsatellite instability-high (MSI-H) cancers. Despite its therapeutic promise, the conformational dynamics that enable WRN to unwind DNA, and how inhibitors disrupt this activity, remains poorly understood. Here, we present crystal structures of apo WRN and WRN bound to single-stranded DNA (ssDNA), capturing key conformations in the helicase catalytic cycle. These structures reveal how WRN engages DNA through conserved polar and aromatic interactions, and how domain rearrangements, including an ordering of the aromatic-rich loop (ARL), drive directional translocation. Biochemical and biophysical data demonstrate how nucleotide and inhibitor binding remodel these conformations and suggest that known clinical inhibitors (HRO761 and VVD-133214) function by locking WRN in inactive, ‘off-DNA’ states. Resistance emerged rapidly in vitro, through acquired point mutations as well as altered WRN expression. Together, our findings provide a structural framework for the WRN structural cycle and support the development of next-generation ‘on-DNA’ inhibitors to overcome resistance

ORGANISM(S): Homo sapiens

PROVIDER: GSE314786 | GEO | 2026/01/30

REPOSITORIES: GEO

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Project description:The RecQ helicase family plays a vital role in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biological importance of RecQ helicases is well established; However, it is still unknown the potential outcomes after DNA damage, and there is no systematic study yet to compare the behavioral changes amongst various RecQ-deficient mice. In this study, we investigated the effects of IR treatment on three RecQ-deficient mouse models (Recql1, Wrn and Recql4). Here we provided evidence that RecQ dysfunction impaired social ability and induced depressive-like behavior in mice, with or without irradiation stress, while abnormal cognitive behaviors only existed in RecQ-deficient mice without IR treatment, suggesting RecQ proteins contribute to mood and cognition. Furthermore, transcripts and metabolomics analysis revealed significant alterations in the RecQ-deficient mice, especially after IR treatment. Particularly, pathways related to neuronal and microglia functions, DNA damage repair, cell cycle, and reactive oxygen response were downregulated in the RecQ4 and Wrn mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our finding suggested that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing it as a potential therapeutic intervention. To understand what Neuroinflammation-related gene expression changes are induced by γ-irradiation in the WT, RecQ1, WRN, RecQ4 deficient mice. They were exposed the whole body with γ-irradiation (IR, 6 Gy), thereafter prefrontal cortex tissues were collected from each mouse and subjected to RNA isolation.

Project description:The RecQ helicase family plays a vital role in maintaining genome stability, including DNA replication, recombination, and DNA repair. In human cells, there are five RecQ helicases: RECQL1, Bloom syndrome (BLM), Werner syndrome (WRN), RECQL4, and RECQL5. Dysfunction or absence of RecQ proteins is associated with genetic disorders, tumorigenesis, premature aging, and neurodegeneration. The biological importance of RecQ helicases is well established; However, it is still unknown the potential outcomes after DNA damage, and there is no systematic study yet to compare the behavioral changes amongst various RecQ-deficient mice. In this study, we investigated the effects of IR treatment on three RecQ-deficient mouse models (Recql1, Wrn and Recql4). Here we provided evidence that RecQ dysfunction impaired social ability and induced depressive-like behavior in mice, with or without irradiation stress, while abnormal cognitive behaviors only existed in RecQ-deficient mice without IR treatment, suggesting RecQ proteins contribute to mood and cognition. Furthermore, transcripts and metabolomics analysis revealed significant alterations in the RecQ-deficient mice, especially after IR treatment. Particularly, pathways related to neuronal and microglia functions, DNA damage repair, cell cycle, and reactive oxygen response were downregulated in the RecQ4 and Wrn mice. In addition, increased DNA damage responses were found in RecQ-deficient mice. Notably, two genes, Aldolase Fructose-Bisphosphate B (Aldob) and NADPH Oxidase 4 (Nox4), were differentially expressed in RecQ-deficient mice. Our finding suggested that RecQ dysfunction contributes to social and depressive-like behaviors in mice, and that aldolase activity may be associated with these changes, representing it as a potential therapeutic intervention. To understand what metabolism-related gene expression changes are induced by γ-irradiation in the WT, RecQ1, WRN, RecQ4 deficient mice. They were exposed the whole body with γ-irradiation (IR, 6 Gy), thereafter prefrontal cortex tissues were collected from each mouse and subjected to RNA isolation.

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Unravelling WRN helicase: Structural Insights Reveal Conformational States and Opportunities for MSI-H Cancer Drug Discovery

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