Tdp1 protects fromtopoisomerase 1–mediated chromosomal breaks inadult zebrafish but is dispensable during larval development

Deficiency in the DNA end-processing enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), causes progressive neuro-degeneration 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.

 

Link to the publication : https://advances.sciencemag.org/content/advances/7/5/eabc4165.full.pdf