Global genomic instability caused by reduced expression of DNA polymerase epsilon in yeast

DNA polymerase epsilon (Pol epsilon) is one of the three replicative eukaryotic DNA polymerases. Pol epsilon deficiency leads to genomic instability and multiple human diseases. Here, we explored global genomic alterations in yeast strains with reduced expression of POL2, the gene that encodes the catalytic subunit of Pol epsilon. Using whole-genome SNP microarray and sequencing, we found that low levels of Pol e elevated the rates of mitotic recombination and chromosomal aneuploidy by two orders of magnitude. Strikingly, low levels of Pol epsilon resulted in a contraction of the number of repeats in the ribosomal DNA cluster and reduced the length of telomeres. These strains also had an elevated frequency of break-induced replication, resulting in terminal loss of heterozygosity. In addition, low levels of Pol epsilon increased the rate of single-base mutations by 13-fold by a Pol xi-dependent pathway. Finally, the patterns of genomic alterations caused by low levels of Pol e were different from those observed in strains with low levels of the other replicative DNA polymerases, Pol alpha and Pol beta, providing further insights into the different roles of the B-family DNA polymerases in maintaining genomic stability.