Mark Glover

Biography

Mark Glover is a professor belongs to the department of biochemistry from the university of Alberta.

Research Interest

. Structural biology of DNA repair complexes. DNA repair proteins and their associated regulatory proteins ensure the integrity of the genome and thereby provide a first line of defence against cancer. We have used a combination of structural and biochemical approaches to probe the function of proteins involved in the cellular response to DNA damage. A. BRCA1 BRCT domain. The C-terminal, BRCT domain of BRCA1 is essential to its tumour suppressor function. BRCT domains are found in a large number of proteins that regulate DNA repair, where these domains act as multi-purpose protein-protein interaction modules. We were the first to determine the structure of the BRCA1 BRCT domain (Williams et al., 2001), and have carried out a detailed analysis of the structural and functional defects associated with a large panel of BRCA1 mutations derived from breast cancer screening programs (Williams et al., 2003; Williams and Glover, 2003). We determined the structure of the BRCA1 BRCT bound to a phospho-peptide target, revealing the structural basis for the biochemical function of this domain (Williams et al., 2004). This work suggested that other members of the BRCT protein family might act as phospho-peptide binding modules (reviewed in Glover et al., 2004). For example, we and others have shown that the BRCT protein MDC1 specifically recognizes the phosphorylated tail of the histone variant, H2AX (Lee et al., 2005). Phospho-H2AX is a critical chromatin signal associated with DNA double strand breaks and the recognition of this mark by MDC1 initiates the assembly of other DNA damage signaling and repair proteins at the DNA lesion. Future work will involve determining the structure and function of other BRCT proteins involved in the DNA damage response. We will use this information as a basis for the design of BRCT inhibitors that could provide leads in the development of new anti-cancer drugs. B. Mammalian polynucleotide kinase (PNK). PNK is a key enzyme in the repair of DNA strand breaks, by both the non-homologous end joining, and base excision/single strand break repair pathways. We determined the crystal structure of the intact enzyme, revealing distinct kinase and phosphatase catalytic domains, and a distinct regulatory FHA domain (Bernstein et al., 2005). Our structure of the FHA domain bound to the scaffold protein XRCC4 reveals how PNK is recruited to sites of repair. We have also characterized the distinct DNA substrate preferences for the phosphatase and kinase domains, which indicates that the two domains act independently (Bernstein et al., 2009). Together with our collaborator, Michael Weinfeld (Cross Cancer Institute), we plan to use this information to develop PNK inhibitors that could be lead compounds for new anti-cancer drug development.