title: Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.
abstract: 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 G2phase, 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.
authors.affiliation: Institute of Marine Biology, Ocean College, Zhejiang University, Zhoushan 316021, China.|Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710.
authors.forename: Dao-Qiong
authors.initials: DQ
authors.lastname: Zheng
authors.affiliation: Institute of Microbiology, College of Life Science, Zhejiang University, Hangzhou 310058, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Institute of Microbiology, College of Life Science, Zhejiang University, Hangzhou 310058, China.
authors.forename: Xue-Chang
authors.initials: XC
authors.lastname: Wu
authors.affiliation: Department of Genetics, University of North Carolina, Chapel Hill, NC 27599.
authors.forename: Piotr A
authors.initials: PA
authors.lastname: Mieczkowski
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC 27710; tom.petes@duke.edu.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Petes
mesh_terms: D000782:Aneuploidy; D015825:Chromosomes, Fungal / Q000235:genetics; D056915:DNA Copy Number Variations; D004258:DNA Polymerase III / Q000378:metabolism; D004261:DNA Replication / Q000235:genetics*; D004271:DNA, Fungal / Q000235:genetics* / Q000378:metabolism*; D042822:Genomic Instability; D006801:Humans; D054643:INDEL Mutation; D019656:Loss of Heterozygosity; D009369:Neoplasms / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D017354:Point Mutation; D020641:Polymorphism, Single Nucleotide; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013312:Stress, Physiological; D020080:Tandem Repeat Sequences
chemical_list: D004271:DNA, Fungal; D029701:Saccharomyces cerevisiae Proteins; D004258:DNA Polymerase III
keywords: DNA polymerase; DNA replication stress; genome instability