CHROMOSOMAL REARRANGEMENTS OCCUR IN SACCHAROMYCES-CEREVISIAE RFA1 MUTATOR MUTANTS DUE TO MUTAGENIC LESIONS PROCESSED BY DOUBLE-STRAND-BREAKREPAIR

Three temperature-sensitive S. cerevisiae RFA1 alleles were found to c ause elevated mutation rates. These mutator phenotypes resulted from t he accumulation of base substitutions, frameshifts, gross deletions (8 bp-18 kb), and nonreciprocal translocations. A representative rfa1 mu tation exhibited a growth defect in conjunction with rad51, rad52, or rad10 mutations, suggesting an accumulation of double-strand breaks. r ad10 and rad52 mutations eliminated deletion and translocation formati on, whereas a rad51 mutation increased the frequency of these events a nd 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 repe ats of 2-20 bp, similar to the breakpoint structures observed at trans locations and gross deletions, including LOH events, underlying human cancer and other hereditary diseases.