Zaksauskaite, R., Thomas, R.C., van Eeden, F. et al. (1 more author) (2021) Tdp1 protects from topoisomerase 1–mediated chromosomal breaks in adult zebrafish but is dispensable during larval development. Science Advances, 7 (5). eabc4165. ISSN 2375-2548
Abstract
Deficiency in the DNA end-processing enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), causes progressive neurodegeneration in humans. Here, we generated a tdp1 knockout zebrafish and confirmed the lack of TDP1 activity. In adulthood, homozygotes exhibit hypersensitivity to topoisomerase 1 (Top1) poisons and a very mild locomotion defect. Unexpectedly, embryonic tdp1−/− zebrafish were not hypersensitive to Top1 poisons and did not exhibit increased Top1-DNA breaks. This is in contrast to the hypersensitivity of Tdp1-deficient vertebrate models reported to date. Tdp1 is dispensable in the zebrafish embryo with transcript levels down-regulated in response to Top1-DNA damage. In contrast, apex2 and ercc4 (xpf) transcripts were up-regulated. These findings identify the tdp1−/− zebrafish embryo as the first vertebrate model that does not require Tdp1 to protect from Top1-DNA damage and identify apex2 and ercc4 (xpf) as putative players fulfilling this role. It highlights the requirement of distinct DNA repair factors across the life span of vertebrates.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). (https://creativecommons.org/licenses/by/4.0/) |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Molecular Biology and Biotechnology (Sheffield) |
Funding Information: | Funder Grant number LISTER INSTITUTE OF PREVENTATIVE MEDICINE NONE WELLCOME TRUST (THE) 103844/Z/14/Z ROSETREES TRUST A1749 BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/R015457/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Mar 2021 17:13 |
Last Modified: | 09 Mar 2021 18:10 |
Status: | Published |
Publisher: | American Association for the Advancement of Science (AAAS) |
Refereed: | Yes |
Identification Number: | 10.1126/sciadv.abc4165 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:171500 |