Compromised DNA repair is a common feature of cancers and contributes to loss of genome integrity and tumorigenesis. Research in the Cole lab aims to investigate DNA repair by homologous recombination (HR) pathways and to provide a means of testing chemotherapeutic agents to specifically perturb these pathways.
HR is critically important for the faithful repair of DNA lesions, especially double‐strand breaks (DSBs). Cancer cells frequently show persistent DSBs and over‐reliance upon a single or few DNA repair pathways. This feature provides a potentially powerful approach to specifically target tumor cells, leaving normal cells with a full complement of DNA repair mechanisms relatively unperturbed.
Leveraging this approach requires a detailed mechanistic understanding of the interrelationships between HR pathways in vivo. To this end, our lab takes advantage of meiotic recombination, in which a large number of DSBs are generated at hotspots throughout the genome. In marked contrast to mitosis, meiotic DSBs are repaired preferentially from the homolog. Multiple redundant and semi-redundant HR pathways collaborate to repair meiotic DSBs, and most are conserved with those used in mitosis.
Our assay system provides high-resolution mapping of recombination outcomes on all four chromatids (tetrad analysis) to determine the molecular nature of individual events and to biochemically and genetically delineate contributions from HR pathways. The lab is using this approach to: define the in vivo molecular characteristics of independent DNA repair pathways; discover new components of these pathways; and provide a means of testing chemotherapeutic agents to specifically perturb individual pathways, with a hope to improve cancer therapies.
The top image to the left shows chromosomes during the zygotene stage of prophase I in meiosis. In zygotene, homologous chromosomes begin to align and join together (synapse) at certain places along the chromosome. The next two images display chromosomes during pachytene. In pachytene, genetic material is exchanged between chromosomes through the process of crossing-over, an important step for chromosome segregation.