Double-strand break repair can lead to high frequencies of deletions within short CAG/CTG trinucleotide repeats.
Trinucleotide repeats undergo contractions and expansions in humans, leading in some cases to fatal neurological disorders. The mechanism responsible for these large size variations is unknown, but replication-slippage events are often suggested as a possible source of instability. We constructed a genetic screen that allowed us to detect spontaneous expansions/contractions of a short trinucleotide repeat in yeast. We show that deletion of RAD27, a gene involved in the processing of Okazaki fragments, increases the frequency of contractions tenfold. Repair of a chromosomal double-strand break (DSB) using a trinucleotide repeat-containing template induces rearrangements of the repeat with a frequency 60 times higher than the natural rate of instability of the same repeat. Our data suggest that both gene conversion and single-strand annealing are major sources of trinucleotide repeat rearrangements.
Rosenstiel Center and Department of Biology, Brandeis University, Waltham, MA 02454-9110, USA.
G F
GF
Richard
B
B
Dujon
J E
JE
Haber
D001483:Base Sequence; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair; D004271:DNA, Fungal / Q000737:chemistry / Q000235:genetics; D005785:Gene Conversion; D005838:Genotype; D008957:Models, Genetic; D016296:Mutagenesis; D009690:Nucleic Acid Conformation; D011494:Protein Kinases / Q000235:genetics*; D011995:Recombination, Genetic; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D017384:Sequence Deletion; D013698:Templates, Genetic; D018911:Trinucleotide Repeats
D004271:DNA, Fungal; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1