Insights into the recruitment of BRCA1 to double strand DNA breaks

  • Author / Creator
    Campbell, Stephen J.
  • In response to genomic stress resulting from external and endogenous insults, the cell has acquired a set of complicated pathways that deal with the damage, which are collectively referred to as the DNA damage response (DDR). In order to repair double strand DNA breaks that may have occurred in G2 and M phase of cell growth, the cell employs a pathway called Homologous Recombination (HR) that utilizes the complementary chromatid as a template to ensure that the repair is error free. BReast CAncer 1 (BRCA1), an essential component of HR, is recruited through a large variety of different post translation modifications and protein-protein interactions. Upon recruitment to the site of a DNA double strand break, BRCA1 functions to initiate repair of the damaged strand. The goal of the thesis is to look in detail at the molecular mechanisms involved in certain aspects of BRCA1 recruitment. First, the crystal structures and in vitro activity of the RING Finger containing (RNF) E3-ubiquitin ligases RNF8 and RNF168 are discussed. Next, the peptide binding specificities of the phospho-peptide binding BRCA1 C-terminal (BRCT) domains of BRCA1 and MDC1 are compared. Finally, a preliminary screen to identify synthetic inhibitors of the BRCA1/phospho-peptide interaction is performed, as well as a discussion as to their therapeutic relevance.

  • Subjects / Keywords
  • Graduation date
    Fall 2012
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Mer, Georges (Biochemsitry - Mayo Clinic, Minneapolis, MN)
    • Hazes, Bart (Medical Microbiology and Immunology)
    • Holmes, Charles (Biochemistry)
    • Weinfeld, Michael (Oncology)