Infertility and aneuploidy in mice lacking a type IA DNA topoisomerase IIIβ

We report that disruption of the mouse TOP3beta gene encoding DNA topoisomerase IIIbeta, one of the two mammalian type IA DNA topoisomerases, leads to a progressive reduction in fecundity. The litter size in crosses of top3beta(-/-) mice decreases over time and through successive generations, and this decrease seems to reflect embryonic death rather than impaired fertilization. These observations are suggestive of a gradual accumulation of chromosomal defects in germ cells lacking DNA topoisomerase IIIbeta, and this interpretation is supported by the observation of a high incidence of aneuploidy in the spermatocytes of infertile top3beta(-/-) males. Cytogenetic examination of spermatocytes of wild-type mice also indicates that DNA topoisomerase IIIbeta becomes prominently associated with the asynaptic regions of the XY bivalents during pachytene, and that there is a time lag between the appearance of chromosome-bound DNA topoisomerase IIIbeta and Rad51, a protein known to be involved in an early step of homologous recombination. We interpret these findings, together with the known mechanistic characteristics of different subfamilies of DNA topoisomerases, in terms of a specific role of a type IA DNA topoisomerase in the resolution of meiotic double-Holliday junctions without crossing over. This interpretation is most likely applicable to mitotic cells as well and can explain the universal presence of at least one type IA DNA topoisomerase in all organisms.