Topoisomerase I (Top1) nicks one strand of DNA to relieve torsional stress associated with replication, transcription and chromatin remodeling. The enzyme forms a transient, covalent intermediate with the nicked DNA and stabilization of the cleavage complex (Top1cc) leads to genetic instability. We examined the effect of Top1 loss or Top1cc stabilization on genome-wide mitotic stability and on mitotic crossovers that lead to loss of heterozygosity (LOH) in budding yeast. The level of Top1cc was elevated using the chemotherapeutic drug camptothecin or a mutant form of the enzyme. Whereas loss of Top1 only destabilized ribosomal DNA repeats, Top1cc accumulation was additionally associated with elevated LOH and genome-wide instability. In particular, the Top1cc greatly elevated copy number variation at the CUP1 tandem-repeat locus, consistent with elevated sister chromatid recombination. Molecular examination of LOH events associated with the Top1cc was also consistent with generation of recombination-initiating lesions during or after DNA synthesis. These results demonstrate that the use of topoisomerase inhibitors results in widespread genome instability that may contribute to secondary neoplasms.
Vyšlo v časopise: Genome-Destabilizing Effects Associated with Top1 Loss or Accumulation of Top1 Cleavage Complexes in Yeast. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005098 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005098
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