Chromosomal rearrangements occur in S. cerevisiae rfa1 mutator mutants due to mutagenic lesions processed by double-strand-break repair.
Three temperature-sensitive S. cerevisiae RFA1 alleles were found to cause elevated mutation rates. These mutator phenotypes resulted from the accumulation of base substitutions, frameshifts, gross deletions (8 bp-18 kb), and nonreciprocal translocations. A representative rfa1 mutation exhibited a growth defect in conjunction with rad51, rad52, or rad10 mutations, suggesting an accumulation of double-strand breaks. rad10 and rad52 mutations eliminated deletion and translocation formation, whereas a rad51 mutation increased the frequency of these events and revealed a new class of genetic rearrangements--loss of a portion of a chromosome arm combined with telomere addition. The breakpoints of the translocations and deletions were flanked by imperfect direct repeats of 2-20 bp, similar to the breakpoint structures observed at translocations and gross deletions, including LOH events, underlying human cancer and other hereditary diseases.
Ludwig Institute for Cancer Research, University of California-San Diego School of Medicine, La Jolla 92093, USA.
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D000483:Alleles; D001483:Base Sequence; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D015825:Chromosomes, Fungal / Q000648:ultrastructure*; D004247:DNA / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D004261:DNA Replication; D004271:DNA, Fungal / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004720:Endonucleases / Q000235:genetics; D016368:Frameshift Mutation; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016296:Mutagenesis; D051135:Rad51 Recombinase; D051721:Rad52 DNA Repair and Recombination Protein; D012091:Repetitive Sequences, Nucleic Acid; D051716:Replication Protein A; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins; D015719:Single-Strand Specific DNA and RNA Endonucleases; D013045:Species Specificity; D014178:Translocation, Genetic
D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C497197:RAD52 protein, S cerevisiae; C497167:RPA1 protein, human; D051721:Rad52 DNA Repair and Recombination Protein; D051716:Replication Protein A; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; C495151:RAD51 protein, S cerevisiae; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D004720:Endonucleases; C064162:RAD10 protein, S cerevisiae; D015719:Single-Strand Specific DNA and RNA Endonucleases