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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | zcae030 |
| Tidsskrift | NAR Cancer |
| Vol/bind | 6 |
| Udgave nummer | 3 |
| Antal sider | 24 |
| ISSN | 2632-8674 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We thank David Cortez for advice on iPOND and members of the Taylor lab for advice and comments on the manuscript. C.C.G., S.L., B.M.B., L.N. and A.T. are funded by a Cancer Research UK Programme [C1422/A19842 and C1422/A31334 to S.S.T.]; Medical Research Council [MR/X008088/1 to S.S.T.]; NIHR Manchester Biomedical Research Centre [NIHR203308]; Cancer Research UK Manchester Centre [C147/A25254]; the views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. R.M.B., N.P. and M.D. were supported by studentships from the Wellcome Trust [109329/Z/15/Z, 102171/Z/13/Z]; Medical Research Council, respectively. H.A.A. and M.L.N. are funded by the Novo Nordisk Foundation (NNF) Center for Protein Research [NNF14CC0001, NNF13OC0006477]; Danish Council of Independent Research [2032-00311B]; Danish Cancer Institute [R325-A18824] (both); NNF Copenhagen Bioscience PhD program [NNF19SA0035440 to H.A.A.].
Funding Information:
C.C.G., S.L., B.M.B., L.N. and A.T. are funded by a Cancer Research UK Programme [C1422/A19842 and C1422/A31334 to S.S.T.]; Medical Research Council [MR/X008088/1 to S.S.T.]; NIHR Manchester Biomedical Research Centre [NIHR203308]; Cancer Research UK Manchester Centre [C147/A25254]; the views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. R.M.B., N.P. and M.D. were supported by studentships from the Wellcome Trust [109329/Z/15/Z, 102171/Z/13/Z]; Medical Research Council, respectively. H.A.A. and M.L.N. are funded by the Novo Nordisk Foundation (NNF) Center for Protein Research [NNF14CC0001, NNF13OC0006477]; Danish Council of Independent Research [2032-00311B]; Danish Cancer Institute [R325-A18824] (both); NNF Copenhagen Bioscience PhD program [NNF19SA0035440 to H.A.A.].
Publisher Copyright:
© The Author(s) 2024.