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Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast.

Publication ,  Journal Article
Andersen, SL; Sloan, RS; Petes, TD; Jinks-Robertson, S
Published in: PLoS Genet
April 2015

Topoisomerase 1 (Top1), a Type IB topoisomerase, functions to relieve transcription- and replication-associated torsional stress in DNA. We investigated the effects of Top1 on genome stability in Saccharomyces cerevisiae using two different assays. First, a sectoring assay that detects loss of heterozygosity (LOH) on a specific chromosome was used to measure reciprocal crossover (RCO) rates. Features of individual RCO events were then molecularly characterized using chromosome-specific microarrays. In the second assay, cells were sub-cultured for 250 generations and LOH was examined genome-wide using microarrays. Though loss of Top1 did not destabilize single-copy genomic regions, RCO events were more complex than in a wild-type strain. In contrast to the stability of single-copy regions, sub-culturing experiments revealed that top1 mutants had greatly elevated levels of instability within the tandemly-repeated ribosomal RNA genes (in agreement with previous results). An intermediate in the enzymatic reaction catalyzed by Top1 is the covalent attachment of Top1 to the cleaved DNA. The resulting Top1 cleavage complex (Top1cc) is usually transient but can be stabilized by the drug camptothecin (CPT) or by the top1-T722A allele. We found that increased levels of the Top1cc resulted in a five- to ten-fold increase in RCOs and greatly increased instability within the rDNA and CUP1 tandem arrays. A detailed analysis of the events in strains with elevated levels of Top1cc suggests that recombinogenic DNA lesions are introduced during or after DNA synthesis. These results have important implications for understanding the effects of CPT as a chemotherapeutic agent.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

April 2015

Volume

11

Issue

4

Start / End Page

e1005098

Location

United States

Related Subject Headings

  • Topoisomerase I Inhibitors
  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • RNA, Ribosomal
  • Mutation
  • Genomic Instability
  • Genome, Fungal
  • Developmental Biology
  • DNA Topoisomerases, Type I
  • Crossing Over, Genetic
 

Citation

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Andersen, S. L., Sloan, R. S., Petes, T. D., & Jinks-Robertson, S. (2015). Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast. PLoS Genet, 11(4), e1005098. https://doi.org/10.1371/journal.pgen.1005098
Andersen, Sabrina L., Roketa S. Sloan, Thomas D. Petes, and Sue Jinks-Robertson. “Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast.PLoS Genet 11, no. 4 (April 2015): e1005098. https://doi.org/10.1371/journal.pgen.1005098.
Andersen SL, Sloan RS, Petes TD, Jinks-Robertson S. Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast. PLoS Genet. 2015 Apr;11(4):e1005098.
Andersen, Sabrina L., et al. “Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast.PLoS Genet, vol. 11, no. 4, Apr. 2015, p. e1005098. Pubmed, doi:10.1371/journal.pgen.1005098.
Andersen SL, Sloan RS, Petes TD, Jinks-Robertson S. Genome-destabilizing effects associated with top1 loss or accumulation of top1 cleavage complexes in yeast. PLoS Genet. 2015 Apr;11(4):e1005098.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

April 2015

Volume

11

Issue

4

Start / End Page

e1005098

Location

United States

Related Subject Headings

  • Topoisomerase I Inhibitors
  • Saccharomyces cerevisiae Proteins
  • Saccharomyces cerevisiae
  • RNA, Ribosomal
  • Mutation
  • Genomic Instability
  • Genome, Fungal
  • Developmental Biology
  • DNA Topoisomerases, Type I
  • Crossing Over, Genetic