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.