Modulation of DNA double strand break repair

  • Heyer, Wolf-Dietrich, (PI)

Project: Research project

Description

DNA damage checkpoints coordinate the cellular responses to DNA damage caused by IONIZING RADIATION (IR) and other agents. The use of IR in medical diagnosis and cancer therapy requires full knowledge of the cellular responses to IR-induced DNA damage. DNA damage checkpoints regulate cell cycle progression, DNA damage- induced transcription, and apoptosis, depending on cell type and organism. The importance of DNA damage checkpoints is exemplified by the human cancer predisposition syndrome ataxia telangiectasia, that affects a central kinase in this pathway. DNA repair ultimately ensures survival after DNA damage. Direct functional relationships between DNA damage checkpoints and DNA repair pathways have been postulated, but are not well documented. The major genotoxic damage of IR are DNA double-strand breaks (DSB). Multiple pathways compete for the repair of such lesions and their respective contributions vary between cell types and organisms. Homologous recombination is a ubiquitous pathway to repair DSBs that ensures error-free repair of these lesions. How homologous recombination is regulated is largely unknown. The goal of this proposal is to establish the mechanism of regulation of the recombinational pathway of DSB repair by the DNA damage checkpoints. The focus is on the Rad55 protein of the yeast Saccharomyces cerevisiae, an evolutionarily conserved DSB repair protein with similarity to the human Xrcc2, Xrcc3, Rad51B, Rad51C, and Rad51D proteins. The preliminary studies have shown that Rad55 protein is phosphorylated in response to DNA damage, dependent on the DNA damage checkpoints. We suspect that this DNA damage-induced phosphorylation is involved in the regulation of recombinational DNA repair. Yeast is particularly well suited for this study, as homologous recombination constitutes the major pathway for DSB repair in this organism. The evolutionary conservation of the major DNA damage checkpoints proteins and DNA repair proteins, including Rad55 protein, suggests that yeast will serve as a paradigmatic model system. The specific aims are: (1) Identification of the mechanism responsible for induced phosphorylation of Rad55 protein. (2) Establishing the biological function of DNA damage-induced Rad55 phosphorylation. (3) Determining the molecular mechanism of checkpoint-mediated modulation of the recombinational repair pathway. (4) Understanding the role of the DNA damage checkpoints in sensing DNA damage for the recombinational DNA repair pathway.
StatusActive
Effective start/end date7/1/013/31/21

Funding

  • National Institutes of Health: $260,105.00
  • National Institutes of Health: $266,948.00
  • National Institutes of Health: $267,277.00
  • National Institutes of Health: $387,948.00
  • National Institutes of Health: $243,089.00
  • National Institutes of Health: $69,901.00
  • National Institutes of Health: $277,166.00
  • National Institutes of Health: $233,281.00
  • National Institutes of Health: $274,781.00
  • National Institutes of Health: $387,948.00
  • National Institutes of Health: $268,082.00
  • National Institutes of Health: $270,789.00
  • National Institutes of Health: $252,060.00
  • National Institutes of Health: $242,953.00
  • National Institutes of Health: $306,694.00

Fingerprint

Double-Stranded DNA Breaks
DNA Damage
Post Translational Protein Processing
Phosphotransferases
Recombinational DNA Repair
Phosphorylation
DNA Repair
Genomic Instability
Homologous Recombination
Genetic Recombination
Neoplasms
Ionizing Radiation
Yeasts
Molecular Biology
Ataxia Telangiectasia
Fungal Proteins

Keywords

  • Medicine(all)