DNA Damage and Repair: Implications for Tumor Formation
Damage to our DNA drives the progression of cancer, aging, and other human diseases. The integrity of our genome is especially at risk while it is being replicated, as the replication machinery often collides with obstacles on DNA, resulting in DNA breaks and chromosomal abnormalities—key events in cancer initiation.
Marcus B. Smolka, Molecular Biology and Genetics, is investigating how cells replicate their genome and how DNA damage occurring during the replication process is repaired. These studies will have direct implications in understanding the mechanisms of tumorigenesis, especially in individuals with mutations in BRCA1, one of the most frequently mutated genes in hereditary breast and ovarian cancer.
DNA replication occurs at structures known as replication forks. As forks move through our genome, copying DNA, they can stall or collapse when encountering obstacles. The proper repair of damaged replication forks involves homologous recombination (HR)-based mechanisms, where sequences of the DNA serve as a template for error-free DNA repair. This prevents genomic instabilities resulting from replication stress.
Mutations in the HR machinery have been associated with extensive genomic instability and cancer predisposition. Smolka’s group is investigating a new mechanism for regulation of DNA repair during DNA replication, examining the central but largely unexplored role of a protein, TopBP1, in the control of HR-mediated repair.
The studies will reveal novel mechanisms of recombinational repair and elucidate how cells choose HR-repair over other repair pathways. This will have implications in the study of tumorigenesis caused by dysfunctions in HR repair and should help in the design of better therapies that target specific DNA repair deficiencies in cancer cells. NIH Award Number: 2R01GM097272-06