Nucleotide excision repair deficiency causes elevated levels of chromosome gain in Saccharomyces cerevisiae

Abstract

Aneuploidy is the most frequent aberration observed in tumor cells, and underlies many debilitating and cancer-prone congenital disorders. Aneuploidy most often arises as a consequence of chromosomal non-disjunction, however, little is known about the genetic and epigenetic factors that affect the chromosomal segregation process. As many cancer-prone syndromes are associated with defects in DNA repair pathways we decided to investigate the relationship between DNA repair in mutation avoidance pathways, namely base and nucleotide excision, and mismatch repair (MMR), and aneuploidy in the yeast Saccharomyces cerevisiae. Isogenic haploid and diploid DNA repair deficient yeast strains were constructed, and spontaneous levels of intra- and inter-chromosomal recombination, forward mutation, chromosome gain, and loss were measured. We show that the nucleotide excision repair (NER) pathway is required for accurate chromosomal disjunction. In the absence of Rad1, Rad2, or Rad4, spontaneous levels of chromosome XV gain were significantly elevated in both haploid and diploid mutant strains. Thus, chromosome gain may be an additional cancer predisposing event in NER deficient patients.