DNA damage-induced regulation of base excision repair by dynamic localization

Summary

Principal Investigator: NICHOLAS CHRISTOPHER BAUER
Abstract: DESCRIPTION (provided by applicant): Cancer, one of the leading causes of death in the United States, is often associated with defects in the major DNA repair systems critical for maintaining genomic integrity. Dysregulation of DNA repair and accumulation of DNA damage is also implicated in the aging process. Base excision repair (BER) is the main line of defense against the most common and mutagenic forms of spontaneous and induced DNA damage. In eukaryotes, many BER proteins are shared by nuclei and mitochondria. While the biochemical operational steps of this important repair pathway have been described in detail, virtually nothing is known about the mechanisms that regulate BER protein localization to the nucleus and/or mitochondria. Organelle-specific DNA damage signals may direct these low-abundance proteins to the appropriate compartment when needed. Since DNA repair and localization mechanisms are highly conserved, the powerful model system Saccharomyces cerevisiae is well-suited for studying both protein localization and DNA repair. An S. cerevisiae BER glycosylase which removes oxidized pyrimidines and is shared by nuclei and mitochondria, Ntg1, appears to be regulated through dynamic localization. I hypothesize that dynamic localization is a general mode of regulation for BER and that DNA repair intermediates produced in the early steps of the BER pathway (e.g. abasic sites) are involved in signaling the presence of DNA damage. This hypothesis will be addressed through two specific aims. Aim 1 will investigate the generality of dynamic compartmentalization by examining the localization of GFP-tagged BER proteins (Ung1, Ogg1, Apn1) in response to preferential genotoxic stress to nuclei or mitochondria. Aim 2 will examine the localization of Ntg1-GFP in cells which have been genetically manipulated to have compartment- specific increases of early BER intermediates to determine whether these intermediates play a role in signaling for dynamic localization. Our long-term goal is to elucidate the signaling pathways that respond to the presence of DNA damage in nuclei or mitochondria, determine how the signals exert their effects, and understand how dysregulation of BER can lead to disease. Furthermore, delineating these signaling pathways will provide valuable insights into the general regulation of nucleomitochondrial signaling and protein localization.
Funding Period: 2012-08-01 - 2014-07-31
more information: NIH RePORT

Top Publications

  1. pmc Automated quantification of the subcellular localization of multicompartment proteins via Q-SCAn
    Nicholas C Bauer
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
    Traffic 14:1200-8. 2013

Detail Information

Publications1

  1. pmc Automated quantification of the subcellular localization of multicompartment proteins via Q-SCAn
    Nicholas C Bauer
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, 30322, USA Graduate Program in Biochemistry, Cell, and Developmental Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
    Traffic 14:1200-8. 2013
    ..Our findings demonstrate the utility of Q-SCAn for quantitative analysis of the subcellular distribution of multicompartment proteins. ..

Research Grants30

  1. ROS sensing and signaling in lifespan regulation
    Elizabeth A Schroeder; Fiscal Year: 2013
    ..Completion of this proposal will identify genes and processes that respond to mROS to regulate yeast lifespan, and may therefore identify targets for therapies and interventions to increase cellular lifespan and human health-span. ..
  2. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  3. HDNA2 IN DNA REPLICATION AND TELOMERE STABILITY
    Sheila A Stewart; Fiscal Year: 2013
    ....
  4. Center for Neuroplasticity at the University of Puerto Rico
    Steven N Treistman; Fiscal Year: 2013
    ..This UPR COBRE Center should define pathways and benchmarks for basic and translational research across the UPR system for the next decades. ..
  5. The molecular basis of RECQ4-associated genetic disorders and cancer predispositi
    Yilun Liu; Fiscal Year: 2013
    ..Crucially, our detailed knowledge on the DNA replication factors will aid in the discovery of new cancer therapy treatments, since inhibiting DNA replication factors effectively prevents cell proliferation. ..
  6. Preferential single-strand break repair in the active genes of mammalian cells
    Tapas K Hazra; Fiscal Year: 2013
    ..Our long-term goal is to determine the mechanistic basis for the development of Ataxia and to develop new strategies for the prevention or treatment of MJD/SCA3 in the human population. ..
  7. Roles for Mismatch Repair Proteins in Maintaining Genome Stability
    ERIC E ALANI; Fiscal Year: 2013
    ....
  8. Enhancing radiation and cisplatin HNSCC cell killing by inhibiting mitochondrial
    Lynn Harrison; Fiscal Year: 2013
    ..Specific Aim 2 ..
  9. Repair of Oxidatively Damaged Guanines
    A LIEN L LU-CHANG; Fiscal Year: 2013
    ..These studies will advance our understanding of carcinogenesis process and form the background work for the development of new anti-cancer drugs. ..
  10. Exploration of Genome Stability as a Therapeutic Target in Cancer
    Rahul Nene; Fiscal Year: 2013
    ..I expect these experiments will provide a rational approach to identify a highly enriched set of new targets for future therapeutic development. ..
  11. Mechanism of Eukaryotic Environmental Mutagenesis
    Graham C Walker; Fiscal Year: 2013
    ....
  12. DNA Damage and Response in the Bladder Microenvironment.
    Bradley P Dixon; Fiscal Year: 2013
    ..This may lead to cancer of the bladder, especially in children who have their bladders surgically reconstructed. ..
  13. DNA Repair Deficiency Associated with Obesity and the Metabolic Syndrome
    R Stephen Lloyd; Fiscal Year: 2013
    ..These investigations will examine the role of reduced DNA repair in the onset and progression of these diseases. ..
  14. USC Research Center for Liver Disease
    Neil Kaplowitz; Fiscal Year: 2013
    ....
  15. Simultaneous Targeting of p53 to the Nucleus and Mitochondria for Cancer Therapy
    Carol S Lim; Fiscal Year: 2013
    ..This dual gene therapy is also expected to be beneficial for other types of aggressive cancers that currently have no effective therapies. ..
  16. Roles of Lig3 and XRCC1 Genes in Genome Stability
    Alan E Tomkinson; Fiscal Year: 2013
    ..abstract_text> ..
  17. DEGENERATIVE AND DEMENTING DISEASES OF AGING
    Stanley B Prusiner; Fiscal Year: 2013
    ..The ultimate goal of all the proposed studies is to define the molecular events that feature in the formation of human prions in order to develop therapeutics that cure the human prion diseases. ..
  18. The Therapy of CML
    Richard E Champlin; Fiscal Year: 2013
    ..This is a productive, highly integrated program for development of novel therapies for CML. ..
  19. Cadiorenal and Metabolic Diseases Research Center
    John E Hall; Fiscal Year: 2013
    ..abstract_text> ..