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Intrinsic PARG inhibitor sensitivity is mimicked by TIMELESS haploinsufficiency and rescued by nucleoside supplementation
Coulson-Gilmer, Camilla Littler, Samantha Barnes, Bethany M Brady, Rosie M Anagho, H. A. Pillay, Nisha Dey, Malini Macmorland, William Bronder, Daniel Nelson, Louisa
Coulson-Gilmer, Camilla
Littler, Samantha
Barnes, Bethany M
Brady, Rosie M
Anagho, H. A.
Pillay, Nisha
Dey, Malini
Macmorland, William
Bronder, Daniel
Nelson, Louisa
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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
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2024
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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.