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

Autor:	Coulson-Gilmer C; 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., Littler S; 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., Barnes BM; 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., Brady RM; 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., Anagho HA; Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., Pillay N; 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., Dey M; 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., Macmorland W; 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., Bronder D; 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., Nelson L; 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., Tighe A; 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., Lin WH; Genome Editing Unit, Faculty of Biology, Medicine and Health, University of Manchester, Michael Smith Building, Dover Street, Manchester M13 9PT, UK., Morgan RD; 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., Unwin RD; 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., Nielsen ML; Proteomics program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark., McGrail JC; 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., Taylor SS; 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.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2024 Jul 16; Vol. 6 (3), pp. zcae030. Date of Electronic Publication: 2024 Jul 16 (Print Publication: 2024).
DOI:	10.1093/narcan/zcae030
Abstrakt:	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. (© The Author(s) 2024. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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