Our genetic material is continually subjected to damage and efficient repair is needed for cancer avoidance. DNA double-strand breaks are cytotoxic and are repaired either by Non Homologous End-Joining or Homologous Recombination (HR). HR provides an important function in DNA repair, where it serves the dual purpose of mending broken chromosomes and recovering sequence information that might be lost at sites of DNA breaks. The recombination process is initiated by exchange of strands between two homologous DNA duplexes (in mitotic cells, recombination generally occurs between two sister chromatids) and the resulting joint molecules can mature into four-way structures known as Holliday junctions. Similar DNA intermediates can be generated during DNA replication via regression of stalled replication forks, which may create a requirement for HJ resolution/dissolution during replication. The primary mechanism of HJ processing involves the BTRR complex which ‘dissolves’ HJs to form non-crossovers, a reaction that is critical to avoid loss of heterozygosity and tumourigenesis. HJs that persist to the late stages of the cell cycle are resolved by the structure-specific endonucleases MUS81-EME1, SLX1-SLX4 or GEN1. Our goal is to address the mechanism of action of the BTRR complex during dHJ dissolution. Understanding this process will further our knowledge of the cancer predisposition disease Bloom’s Syndrome, and will expand our understanding of the relationships between defects in recombinational repair and tumourigenesis.
To gain insight into the mechanism of HJ processing by the BTRR complex we will:
1. Determine the molecular mechanism of HJ dissolution using structural and biochemical approaches.
2. Define the interaction surfaces between components of the BTRR complex and how these interactions contribute to the HJ dissolution.
3. Determine the importance of BLM/BTRR dimer formation for in vivo functionality and correlate with mutations found in BS patients.
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