Abstract
Most cells of solid tumors have very high levels of genome instability of several different types, including deletions, duplications, translocations, and aneuploidy. Much of this instability appears induced by DNA replication stress. As a model for understanding this type of instability, we have examined genome instability in yeast strains that have low levels of two of the replicative DNA polymerases: DNA polymerase α and DNA polymerase δ (Polα and Polδ). We show that low levels of either of these DNA polymerases results in greatly elevated levels of mitotic recombination, chromosome rearrangements, and deletions/duplications. The spectrum of events in the two types of strains, however, differs in a variety of ways. For example, a reduced level of Polδ elevates single-base alterations and small deletions considerably more than a reduced level of Polα. In this review, we will summarize the methods used to monitor genome instability in yeast, and how this analysis contributes to understanding the linkage between genome instability and DNA replication stress.
Highlights
The accurate duplication of genetic material is essential for life, and three B-family DNA polymerases (Pol α, δ, and ε) are critical for genome replication in the yeast Saccharomyces cerevisiae, as in other eukaryotes [1]
We show the chromosome segregation pattern that results in loss of heterozygosity (LOH)
The terminal and interstitial LOH events in both the low Polα or Polδ strains were widely distributed through the genome. In both types of strains, at the breakpoints of the LOH events, we found an overrepresentation of chromosome elements known to be associated with stalled or slow-moving replication forks, even under normal growth conditions
Summary
The accurate duplication of genetic material is essential for life, and three B-family DNA polymerases (Pol α, δ, and ε) are critical for genome replication in the yeast Saccharomyces cerevisiae, as in other eukaryotes [1]. One property in common among many of these motifs is their tendency to stall replication forks, likely related to their ability to form secondary DNA structures (hairpins, triplex DNA, G-quadruplexes) [8] Both tracts of the trinucleotide CTG (capable of forming hairpin structures) and GAA tracts (associated with triplex formation) result in elevated levels of double-strand breaks and hyper-recombination [9,10,11]. As described below, regions that are preferred sites for recombinogenic lesions under conditions of replication stress often co-localize with sites at which replication forks are slowed, or stalled, even under normal growth conditions [12,13]
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