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 a few key DNA repair pathways. This over-reliance creates an opportunity to develop approaches that specifically target repair pathways in tumor cells, while leaving normal cells relatively unperturbed.
Leveraging this approach requires a detailed mechanistic understanding of the interrelationships between HR pathways in vivo. To this end, the Cole lab takes advantage of a unique mouse model of meiotic recombination. During meiosis, 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.
The lab's 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 on the right 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.