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    Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation

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    Authors
    Coulson-Gilmer, Camilla
    Littler, Samantha
    Barnes, Bethany M
    Brady, Rosie M
    Anagho, H. A.
    Pillay, Nisha
    Dey, Malini
    Macmorland, William
    Bronder, Daniel
    Nelson, Louisa
    Tighe, Anthony
    Lin, W. H.
    Morgan, Robert D
    Unwin, Richard D
    Nielsen, M. L.
    McGrail, Joanne C
    Taylor, Stephen S
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    Affiliation
    Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre (MAHSC), Manchester Cancer Research Centre, Wilmslow Road, Manchester M20 4GJ, UK Department of Medical Oncology, The Christie NHS Foundation Trust, Wilmslow Rd, Manchester M20 4BX, UK
    Issue Date
    2024
    
    Metadata
    Show full item record
    Abstract
    A subset of cancer cells are intrinsically sensitive to inhibitors targeting PARG, the poly(ADP-ribose) glycohydrolase that degrades PAR chains. Sensitivity is accompanied by persistent DNA replication stress, and can be induced by inhibition of TIMELESS, a replisome accelerator. However, the nature of the vulnerability responsible for intrinsic sensitivity remains undetermined. To understand PARG activity dependency, we analysed Timeless model systems and intrinsically sensitive ovarian cancer cells. We show that nucleoside supplementation rescues all phenotypes associated with PARG inhibitor sensitivity, including replisome speed and fork stalling, S-phase completion and mitotic entry, proliferation dynamics and clonogenic potential. Importantly nucleoside supplementation restores PARG inhibitor resistance despite the continued presence of PAR chains, indicating that sensitivity does not correlate with PAR levels. In addition, we show that inhibition of thymidylate synthase, an enzyme required for dNTP homeostasis, induces PARG-dependency. Together, these observations suggest that PARG inhibitor sensitivity reflects an inability to control replisome speed and/or maintain helicase-polymerase coupling in response to nucleotide imbalances. Graphical Abstract
    Citation
    Coulson-Gilmer C, Littler S, Barnes BM, Brady RM, Anagho HA, Pillay N, et al. Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation. NAR cancer. 2024 JUL 16;6(3). PubMed PMID: WOS:001271086900001. English.
    Journal
    NAR Cancer
    URI
    http://hdl.handle.net/10541/627130
    PubMed ID
    39015544
    Language
    en
    Collections
    All Christie Publications

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