Rudd, S.G., Gad, H. orcid.org/0000-0001-6530-1443, Sanjiv, K. et al. (7 more authors) (2020) MTH1 inhibitor TH588 disturbs mitotic progression and induces mitosis-dependent accumulation of genomic 8-oxodG. Cancer Research, 80 (17). pp. 3530-3541. ISSN 0008-5472
Abstract
Reactive oxygen species (ROS) oxidize nucleotide triphosphate pools (e.g., 8-oxodGTP), which may kill cells if incorporated into DNA. Whether cancers avoid poisoning from oxidized nucleotides by preventing incorporation via the oxidized purine diphosphatase MTH1 remains under debate. Also, little is known about DNA polymerases incorporating oxidized nucleotides in cells or how oxidized nucleotides in DNA become toxic. Here we show that replacement of one of the main DNA replicases in human cells, DNA polymerase delta (Pol δ), with an error-prone variant allows increased 8-oxodG accumulation into DNA following treatment with TH588, a dual MTH1 inhibitor (MTH1i) and microtubule targeting agent. The resulting elevated genomic 8-oxodG correlated with increased cytotoxicity of TH588. Interestingly, no substantial perturbation of replication fork progression was observed, but rather mitotic progression was impaired and mitotic DNA synthesis triggered. Reducing mitotic arrest by reversin treatment prevented accumulation of genomic 8-oxodG and reduced cytotoxicity of TH588, in line with the notion that mitotic arrest is required for ROS buildup and oxidation of the nucleotide pool. Furthermore, delayed mitosis and increased mitotic cell death was observed following TH588 treatment in cells expressing the error-prone but not wild type Pol δ variant, which is not observed following treatments with anti-mitotic agents. Collectively, these results link accumulation of genomic oxidized nucleotides with disturbed mitotic progression.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2020, American Association for Cancer Research. This is an author-produced version of a paper subsequently published in Cancer Research. Uploaded in accordance with the publisher's self-archiving policy. |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 05 Jun 2020 12:04 |
Last Modified: | 12 Nov 2021 11:25 |
Status: | Published |
Publisher: | American Association for Cancer Research (AACR) |
Refereed: | Yes |
Identification Number: | 10.1158/0008-5472.can-19-0883 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:161626 |