+1 Recommend
1 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Increased LOH Due to Defective Sister Chromatid Cohesion Is Due Primarily to Chromosomal Aneuploidy and Not Recombination

      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.


          Loss of heterozygosity (LOH) is an important factor in cancer, pathogenic fungi, and adaptation to changing environments. The sister chromatid cohesion process (SCC) suppresses aneuploidy and therefore whole chromosome LOH. SCC is also important to channel recombinational repair to sister chromatids, thereby preventing LOH mediated by allelic recombination. There is, however, insufficient information about the relative roles that the SCC pathway plays in the different modes of LOH. Here, we found that the cohesin mutation mcd1-1, and other mutations in SCC, differentially affect the various types of LOH. The greatest effect, by three orders of magnitude, was on whole chromosome loss (CL). In contrast, there was little increase in recombination-mediated LOH, even for telomeric markers. Some of the LOH events that were increased by SCC mutations were complex, i.e., they were the result of several chromosome transactions. Although these events were independent of POL32, the most parsimonious way to explain the formation of at least some of them was break-induced replication through the centromere. Interestingly, the mcd1-1 pol32Δ double mutant showed a significant reduction in the rate of CL in comparison with the mcd1-1 single mutant. Our results show that defects in SCC allow the formation of complex LOH events that, in turn, can promote drug or pesticide resistance in diploid microbes that are pathogenic to humans or plants.

          Related collections

          Most cited references 49

          • Record: found
          • Abstract: found
          • Article: not found

          A constant rate of spontaneous mutation in DNA-based microbes.

           W Drake (1991)
          In terms of evolution and fitness, the most significant spontaneous mutation rate is likely to be that for the entire genome (or its nonfrivolous fraction). Information is now available to calculate this rate for several DNA-based haploid microbes, including bacteriophages with single- or double-stranded DNA, a bacterium, a yeast, and a filamentous fungus. Their genome sizes vary by approximately 6500-fold. Their average mutation rates per base pair vary by approximately 16,000-fold, whereas their mutation rates per genome vary by only approximately 2.5-fold, apparently randomly, around a mean value of 0.0033 per DNA replication. The average mutation rate per base pair is inversely proportional to genome size. Therefore, a nearly invariant microbial mutation rate appears to have evolved. Because this rate is uniform in such diverse organisms, it is likely to be determined by deep general forces, perhaps by a balance between the usually deleterious effects of mutation and the physiological costs of further reducing mutation rates.
            • Record: found
            • Abstract: found
            • Article: not found

            A direct link between sister chromatid cohesion and chromosome condensation revealed through the analysis of MCD1 in S. cerevisiae.

            The S. cerevisiae MCD1 (mitotic chromosome determinant) gene was identified in genetic screens for genes important for chromosome structure. MCD1 is essential for viability and homologs are found from yeast to humans. Analysis of the mcd1 mutant and cell cycle-dependent expression pattern of Mcd1p suggest that this protein functions in chromosome morphogenesis from S phase through mitosis. The mcd1 mutant is defective in sister chromatid cohesion and chromosome condensation. The physical association between Mcd1p and Smc1p, one of the SMC family of chromosomal proteins, further suggests that Mcd1p functions directly on chromosomes. These data implicate Mcd1p as a nexus between cohesion and condensation. We present a model for mitotic chromosome structure that incorporates this previously unsuspected link.
              • Record: found
              • Abstract: found
              • Article: not found

              Srs2 and Sgs1-Top3 suppress crossovers during double-strand break repair in yeast.

              Very few gene conversions in mitotic cells are associated with crossovers, suggesting that these events are regulated. This may be important for the maintenance of genetic stability. We have analyzed the relationship between homologous recombination and crossing-over in haploid budding yeast and identified factors involved in the regulation of crossover outcomes. Gene conversions unaccompanied by a crossover appear 30 min before conversions accompanied by exchange, indicating that there are two different repair mechanisms in mitotic cells. Crossovers are rare (5%), but deleting the BLM/WRN homolog, SGS1, or the SRS2 helicase increases crossovers 2- to 3-fold. Overexpressing SRS2 nearly eliminates crossovers, whereas overexpression of RAD51 in srs2Delta cells almost completely eliminates the noncrossover recombination pathway. We suggest Sgs1 and its associated topoisomerase Top3 remove double Holliday junction intermediates from a crossover-producing repair pathway, thereby reducing crossovers. Srs2 promotes the noncrossover synthesis-dependent strand-annealing (SDSA) pathway, apparently by regulating Rad51 binding during strand exchange.

                Author and article information

                G3 (Bethesda)
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes, Genomes, Genetics
                G3: Genes|Genomes|Genetics
                Genetics Society of America
                03 October 2017
                October 2017
                : 7
                : 10
                : 3305-3315
                [* ]Department of Plant Pathology and Microbiology, Hebrew University, Rehovot 76100, Israel
                []Chromosome Stability Group, Laboratory or Molecular Genetics, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina 27709
                Author notes
                [1 ]Corresponding author: Hebrew University Robert H. Smith Faculty of Agriculture, PO box 12, Rehovot 76100, Israel. E-mail: shay.covo@ 123456mail.huji.ac.il
                Copyright © 2017 Sagi et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 52, Pages: 11



                Comment on this article