Telomere-related functions of yeast KU in the repair of bleomycin-induced DNA damage

Biochem Biophys Res Commun. 2007 Jun 8;357(3):800-3. doi: 10.1016/j.bbrc.2007.04.011. Epub 2007 Apr 10.

Abstract

Bleomycins are small glycopeptide cancer chemotherapeutics that give rise to 3'-modified DNA double-strand breaks (DSBs). In Saccharomyces cerevisiae, DSBs are predominantly repaired by RAD52-dependent homologous recombination (HR) with some support by Yku70/Yku80 (KU)-dependent pathways. The main DSB repair function of KU is believed to be as part of the non-homologous end-joining (NHEJ) pathway, but KU also functions in a "chromosome healing" pathway that seals DSBs by de novo telomere addition. We report here that rad52Deltayku70Delta double mutants are considerably more bleomycin hypersensitive than rad52Deltalig4Delta cells that lack the NHEJ-specific DNA ligase 4. Moreover, the telomere-specific KU mutation yku80-135i also dramatically increases rad52Delta bleomycin hypersensitivity, almost to the level of rad52Deltayku80Delta. The results indicate that telomere-specific functions of KU play a more prominent role in the repair of bleomycin-induced damage than its NHEJ functions, which could have important clinical implications for bleomycin-based combination chemotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / toxicity
  • Antigens, Nuclear / genetics
  • Antigens, Nuclear / physiology*
  • Bleomycin / toxicity*
  • DNA Damage*
  • DNA Ligase ATP
  • DNA Ligases / genetics
  • DNA Ligases / physiology
  • DNA Repair / genetics
  • DNA Repair / physiology*
  • DNA, Fungal / drug effects
  • DNA, Fungal / genetics
  • DNA, Fungal / metabolism
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / physiology*
  • Ku Autoantigen
  • Microbial Viability / drug effects
  • Microbial Viability / genetics
  • Mutation
  • Rad52 DNA Repair and Recombination Protein / genetics
  • Rad52 DNA Repair and Recombination Protein / physiology
  • Recombination, Genetic
  • Saccharomyces cerevisiae / drug effects
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / physiology
  • Telomere / genetics
  • Telomere / metabolism*

Substances

  • Antibiotics, Antineoplastic
  • Antigens, Nuclear
  • DNA, Fungal
  • DNA-Binding Proteins
  • RAD52 protein, S cerevisiae
  • Rad52 DNA Repair and Recombination Protein
  • Saccharomyces cerevisiae Proteins
  • Bleomycin
  • Ku Autoantigen
  • DNA Ligases
  • DNA Ligase ATP