Inverted repeat-stimulated sister-chromatid exchange events are RAD1-independent but reduced in a msh2 mutant.
Inverted repeats (IRs) and trinucleotide repeats (TNRs) that have the potential to form secondary structures in vivo are known to cause genome rearrangements. Expansions of TNRs in humans are associated with several neurological disorders. Both IRs and TNRs stimulate spontaneous unequal sister-chromatid exchange (SCE) in yeast. Secondary structure-associated SCE events occur via double-strand break repair. Here we show that the rate of spontaneous IR-stimulated unequal SCE events in yeast is significantly reduced in strains with mutations in the mismatch repair genes MSH2 or MSH3, but unaffected by a mutation in the nucleotide excision-repair gene RAD1. Non-IR-associated unequal SCE events are increased in both MMR- and rad1-mutant cells; however, SCE events for both IR- and non-IR-containing substrates occur at a higher level in the exo1 background. Our results suggest that spontaneous SCE occurs by a template switching mechanism. Like IRs, TNRs have been shown to generate double-strand breaks (DSBs) in yeast. TNR expansions in mice are MSH2-dependent. Since IR-mediated SCE events are reduced in msh2 cells, we propose that TNR expansion mutations arise when DSBs are repaired using the sister or the homolog as a template.
Nag
Dilip K
DK
Molecular Genetics Program, Wadsworth Center, Center for Medical Sciences 150 New Scotland Avenue, Albany, NY 12208, USA.
Fasullo
Michael
M
Dong
Zheng
Z
Tronnes
Ashlie
A
D004249:DNA Damage; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004271:DNA, Fungal / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004720:Endonucleases / Q000235:genetics / Q000502:physiology*; D005090:Exodeoxyribonucleases / Q000235:genetics; D005656:Fungal Proteins / Q000502:physiology; D051718:MutS Homolog 2 Protein; D000074081:MutS Homolog 3 Protein; D009154:Mutation; D012091:Repetitive Sequences, Nucleic Acid; D012441:Saccharomyces cerevisiae / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000502:physiology*; D012854:Sister Chromatid Exchange
D004271:DNA, Fungal; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C081696:MSH3 protein, S cerevisiae; D000074081:MutS Homolog 3 Protein; D029701:Saccharomyces cerevisiae Proteins; D004720:Endonucleases; D005090:Exodeoxyribonucleases; C069266:RAD1 protein, S cerevisiae; C028450:exodeoxyribonuclease I; C489751:MSH2 protein, S cerevisiae; D051718:MutS Homolog 2 Protein; D045643:DNA Repair Enzymes