Academic journal article Genetics

The Identification of a Novel Mutant Allele of Topoisomerase II in Caenorhabditis Elegans Reveals a Unique Role in Chromosome Segregation during Spermatogenesis

Academic journal article Genetics

The Identification of a Novel Mutant Allele of Topoisomerase II in Caenorhabditis Elegans Reveals a Unique Role in Chromosome Segregation during Spermatogenesis

Article excerpt

TYPE II DNA topoisomerases play a critical role in chromosome fidelity by alleviating topological stresses that arise within chromosomes. Eukaryotic type II topoisomerases (topoisomerase II) are structurally and functionally conserved (Holm et al. 1985; Drake et al. 1989; Ramos et al. 2011). Topoisomerase II is a large ATP-dependent, homodimeric enzyme. Each subunit breaks one DNA strand, passes a second unbroken strand through the break, and then reseals the break (reviewed in Nitiss 2009). Thus, during mitotic divisions, topoisomerase II enzymes solve topological problems that arise during replication, transcription, sister chromatid segregation, and recombination. Topoisomerase II is also crucial for the maintenance of mitotic chromosome structure. In mammals and yeast, it is found along the chromosome axes and knock down by either mutation or RNA interference (RNAi) in mammals, yeast, and Drosophila leads to chromosome condensation defects (Earnshawetal. 1985; Gasseretal. 1986; Uemura et al. 1987; Xu and Manley 2007; Mengoli et al. 2014).

Although the actions of topoisomerase II in mitosis have been well characterized, studies investigating the roles of topoisomerase II during meiosis are emerging. Unlike mitosis, which has a single round of DNA replication followed by one round of chromosome segregation, meiosis consists of a single round of DNA replication followed by two rounds of chromosome segregation. During the first meiotic division, homologous chromosomes pair, synapse, and form physical connections through recombination that, in partnership with sister chromatid cohesion, aid in the segregation of the homolog pairs (reviewed in Hillers et al. 2015; Zickler and Kleckner 2015). The second meiotic division is similar to mitosis with respect to the segregation of sister chromatids. Due to the requirement for topoisomerase II during mitosis, most strong loss-of-function mutations are lethal, limiting studies during meiosis. Shifting temperature-sensitive mutants of diploid Saccharomyces cerevisiae and Schizosaccharomyces pombe top2 to a nonpermissive temperature leads to a cell-cycle arrest during meiosis I (Rose et al. 1990; Hartsuiker et al. 1998). Meiosis-specific Top2 RNAi in Drosophila results in sterility due to defects in homolog segregation (Hughes and Hawley 2014). Topoisomerase II inhibitors in male and female mouse meiosis lead to defects in chromosome condensation and segregation during the first meiotic division (Marchetti et al. 2001; Li et al. 2013; Gómez et al. 2014). Taken together, these studies demonstrate that topoisomerase II also plays a critical role in the segregation of homologs during meiosis I. Localization studies in yeast and mammals have demonstrated that, as in mitosis, topoisomerase II localizes along the chromosome axes of meiosis I chromosomes (Klein etal. 1992; Li etal. 2013;Gómez etal. 2014). Besides these data, the mechanism of topoisomerase II action and regulation during meiosis and its interaction with the vast and diverse molecular machinery needed to pair, synapse, link, and segregate homologous chromosomes have not been solved.

In Caenorhabditis elegans, a single gene encodes the topoisomerase II homolog, top-2. TOP-2 shares 52% amino acid sequence identity with human topoisomerase IIa. Within the C. elegans genome, a recent duplication event gave rise to a top-2 paralog called cin-4, however, this gene lacks the ATPase domain and is unlikely to have enzymatic function (Stanvitch and Moore 2008). Our genetic studies further suggest that cin-4 is not essential for embryonic or germ-line development. Previous studies found that RNAi depletion of top-2 results in chromosome nondisjunction during embryonic mitotic divisions (Bembenek et al. 2013). In another analysis, top-2 RNAi uncovered a role for TOP-2 in generating the DNA damage that occurs at the onset of zygotic genome activation in the primordial germ cells of embryos (Butuci et al. 2015). While these two studies have demonstrated that, similar to other organisms, C. …

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