Tdp1 protects from topoisomerase 1-mediated chromosomal breaks in adult zebrafish but is dispensable during larval development

• Published in: Science advances Vol. 7; no. 5
• Main Authors: Zaksauskaite, Ringaile, Thomas, Ruth C, van Eeden, Freek, El-Khamisy, Sherif F
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 29.01.2021
• Subjects: Animals; Chromosome Breakage; Diseases and Disorders; DNA Repair; Phosphoric Diester Hydrolases - genetics; Phosphoric Diester Hydrolases - metabolism; Poisons; SciAdv r-articles; Zebrafish - genetics; Zebrafish - metabolism
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.abc4165

Deficiency in the DNA end-processing enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), causes progressive neurodegeneration in humans. Here, we generated a 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 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, and ( ) transcripts were up-regulated. These findings identify the zebrafish embryo as the first vertebrate model that does not require Tdp1 to protect from Top1-DNA damage and identify and ( ) as putative players fulfilling this role. It highlights the requirement of distinct DNA repair factors across the life span of vertebrates.