Differential effect of the overexpression of Rad2/XPG family endonucleases on genome integrity in yeast and human cells

DNA Repair (Amst). 2017 Sep;57:66-75. doi: 10.1016/j.dnarep.2017.06.030. Epub 2017 Jul 3.

Abstract

Eukaryotic cells possess several DNA endonucleases that are necessary to complete different steps in DNA metabolism. Rad2/XPG and Rad27/FEN1 belong to a group of evolutionary conserved proteins that constitute the Rad2 family. Given the important roles carried out by these nucleases in DNA repair and their capacity to create DNA breaks, we have investigated the effect that in vivo imbalance of these nucleases and others of the family have on genome integrity and cell proliferation. We show that overexpression of these nucleases causes genetic instability in both yeast and human cells. Interestingly, the type of recombination event and DNA damage induced suggest specific modes and timing of action of each nuclease that are beyond their known DNA repair function and are critical to preserve genome integrity. In addition to identifying new sources of genome instability, a hallmark of cancer cells, this study provides new genetic tools for studies of genome dynamics.

Keywords: Genetic instability; Homologous recombination; Rad2/XPG family; Rad27/FEN1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • DNA / metabolism
  • DNA Damage
  • DNA Repair*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Endodeoxyribonucleases / genetics*
  • Endodeoxyribonucleases / metabolism
  • Endonucleases / genetics*
  • Endonucleases / metabolism
  • Flap Endonucleases / genetics*
  • Flap Endonucleases / metabolism
  • Gene Expression Regulation
  • Genomic Instability*
  • Humans
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Saccharomyces cerevisiae / enzymology*
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Up-Regulation

Substances

  • DNA excision repair protein ERCC-5
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • RAD2 protein, S cerevisiae
  • DNA
  • Endodeoxyribonucleases
  • Endonucleases
  • Flap Endonucleases
  • FEN1 protein, human
  • RAD27 protein, S cerevisiae