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Insights into the recruitment of BRCA1 to double strand DNA breaks Open Access


Other title
BRCT inhibition
DNA Damage Response
RING domain
K-63 Ubiquitylation
Type of item
Degree grantor
University of Alberta
Author or creator
Campbell, Stephen J.
Supervisor and department
Glover, Mark (Biochemistry)
Examining committee member and department
Holmes, Charles (Biochemistry)
Mer, Georges (Biochemsitry - Mayo Clinic, Minneapolis, MN)
Weinfeld, Michael (Oncology)
Hazes, Bart (Medical Microbiology and Immunology)
Department of Biochemistry

Date accepted
Graduation date
Doctor of Philosophy
Degree level
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.
Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
Citation for previous publication
Campbell, S.J., ¥Edwards, R.A., ¥Leung, C.C.Y., ¥Neculai, D., Hodge, C.D., Dhe-Paganon, S., and Glover, J.N.M., Structural insights into the function of RNF8 and RNF168 in Ubc13/Mms2-dependent ubiquitylation. J. Biol. Chem., 2012. ¥Equal ContributionCampbell, S.J., Edwards, R.A., and Glover, J.N.M., Comparison of the structures and peptide binding specificities of the BRCT domains of MDC1 and BRCA1. Structure, 2010. 18(2): p. 167-76.Yuan, Z., ¥Kumar, E.A., ¥Campbell, S.J., ¥Palermo, N.Y., Kizhake, S., Glover, J.N.M., Natarajan, A. Exploiting the P-1 pocket of BRCT domains toward a structure guided inhibitor design. ACS Med Chem Lett, 2011. 2(10): p. 764-767. ¥Equal Contribution

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