Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.
DNA replication stress (DRS)-induced genomic instability is an important factor driving cancer development. To understand the mechanisms of DRS-associated genomic instability, we measured the rates of genomic alterations throughout the genome in a yeast strain with lowered expression of the replicative DNA polymerase δ. By a genetic test, we showed that most recombinogenic DNA lesions were introduced during S or G2 phase, presumably as a consequence of broken replication forks. We observed a high rate of chromosome loss, likely reflecting a reduced capacity of the low-polymerase strains to repair double-stranded DNA breaks (DSBs). We also observed a high frequency of deletion events within tandemly repeated genes such as the ribosomal RNA genes. By whole-genome sequencing, we found that low levels of DNA polymerase δ elevated mutation rates, both single-base mutations and small insertions/deletions. Finally, we showed that cells with low levels of DNA polymerase δ tended to accumulate small promoter mutations that increased the expression of this polymerase. These deletions conferred a selective growth advantage to cells, demonstrating that DRS can be one factor driving phenotypic evolution.
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- Tandem Repeat Sequences
- Stress, Physiological
- Sequence Analysis, DNA
- Saccharomyces cerevisiae Proteins
- Saccharomyces cerevisiae
- Polymorphism, Single Nucleotide
- Point Mutation
- Oligonucleotide Array Sequence Analysis
- Neoplasms
- Loss of Heterozygosity
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Tandem Repeat Sequences
- Stress, Physiological
- Sequence Analysis, DNA
- Saccharomyces cerevisiae Proteins
- Saccharomyces cerevisiae
- Polymorphism, Single Nucleotide
- Point Mutation
- Oligonucleotide Array Sequence Analysis
- Neoplasms
- Loss of Heterozygosity