Skip to main content

Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.

Publication ,  Journal Article
Zheng, D-Q; Zhang, K; Wu, X-C; Mieczkowski, PA; Petes, TD
Published in: Proc Natl Acad Sci U S A
December 13, 2016

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.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 13, 2016

Volume

113

Issue

50

Start / End Page

E8114 / E8121

Location

United States

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
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Zheng, D.-Q., Zhang, K., Wu, X.-C., Mieczkowski, P. A., & Petes, T. D. (2016). Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A, 113(50), E8114–E8121. https://doi.org/10.1073/pnas.1618129113
Zheng, Dao-Qiong, Ke Zhang, Xue-Chang Wu, Piotr A. Mieczkowski, and Thomas D. Petes. “Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.Proc Natl Acad Sci U S A 113, no. 50 (December 13, 2016): E8114–21. https://doi.org/10.1073/pnas.1618129113.
Zheng D-Q, Zhang K, Wu X-C, Mieczkowski PA, Petes TD. Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8114–21.
Zheng, Dao-Qiong, et al. “Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae.Proc Natl Acad Sci U S A, vol. 113, no. 50, Dec. 2016, pp. E8114–21. Pubmed, doi:10.1073/pnas.1618129113.
Zheng D-Q, Zhang K, Wu X-C, Mieczkowski PA, Petes TD. Global analysis of genomic instability caused by DNA replication stress in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):E8114–E8121.

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

December 13, 2016

Volume

113

Issue

50

Start / End Page

E8114 / E8121

Location

United States

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