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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Zheng, D-Q; Zhang, K; Wu, X-C; Mieczkowski, PA; Petes, TD

Published Date

  • December 13, 2016

Published In

Volume / Issue

  • 113 / 50

Start / End Page

  • E8114 - E8121

PubMed ID

  • 27911848

Pubmed Central ID

  • 27911848

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.1618129113

Language

  • eng

Conference Location

  • United States