Dovey, M., Patton, E.E., Bowman, T., North, T., Goessling, W., Zhou, Y., and Zon, L.I. (2009) Topoisomerase II alpha is required for embryonic development and liver regeneration in zebrafish. Molecular and cellular biology. 29(13):3746-3753.
Topoisomerases solve the topological problems encountered by DNA throughout the lifetime of a cell. Topoisomerase IIalpha, which is highly conserved among eukaryotes, untangles replicated chromosomes during mitosis and is absolutely required for cell viability. A homozygous lethal mutant, can4, was identified in a screen to identify genes important for cell proliferation in zebrafish by utilizing an antibody against a mitosis specific marker, phospho-histone H3. Mutant embryos have a decrease in the number a proliferating cells and display increases in DNA content and apoptosis, as well as mitotic spindle defects. Positional cloning revealed that the genetic defect underlying these phenotypes was the result of a mutation in the zebrafish topoisomerase IIalpha (top2a) gene. top2a was found to be required for decatenation, but not condensation in embryonic mitoses. In addition to being required for development, top2a was found to be a haploinsufficient regulator of adult liver re-growth in zebrafish. Regeneration analysis of other adult tissues, including fins, revealed no heterozygous phenotype. Our results confirm a conserved role for TOP2A in vertebrates as well as a dose sensitive requirement for top2a in adults.