Understanding mechanisms of DNA breakage and repair is fundamental to cancer research
DNA breakage can be both regulated and unregulated. Regulated DNA breakage originates within the cell during normal processes and is absolutely required for meoitic crossing-over and immune system diversity. In contrast, unregulated DNA breakage can result from exposure to ultraviolet radiation from the sun, chemicals present in the environment, and even the formation of reactive chemical species from reactions between oxygen and water within cells. Moreover, many cancer therapies induce irreparable DNA damage leading to cell death. Thus, understanding how cells respond to and repair DNA damage is important for understanding the causes of cancer and developing new treatments. Epigenetics and Molecular Carcinogenesis researchers are defining:
- Mechanisms of DNA double-strand break repair
- Roles of DNA polymerases in repair
- DNA damage and repair as part of normal cell function and in carcinogenesis
- DNA damage response pathway
- Relationships between chromatin remodeling and DNA damage response and repair
When DNA damage causes cells to go awry
Department investigators are studying the protein machinery involved in several DNA repair pathways, including homologous recombination (HR) and non-homologous end-joining (NHEJ) for the repair of DNA double-strand breaks, and nucleotide excision repair for the repair of ultraviolet radiation-induced DNA damage and other strand-distorting lesions.
Faculty are also learning how programmed DNA damage and repair are involved in normal processes, such as meiosis and B-cell development, and how these processes can go awry during cancer development. Other active areas of research include investigations into how DNA polymerases synthesize new DNA at repair sites, how chromatin-modifying activities cooperate with DNA repair machinery to facilitate repair in the context of chromatin, and the mechanisms underlying the conversion of DNA damage into the mutations that cause cancer.
Defining DNA damage response signaling pathways
Studies in the department are also focused on DNA damage response signaling pathways that induce cell cycle checkpoints and alter transcriptional programs. DNA damage response signaling is critical for maintaining genome integrity and is often inactivated in cancers (e.g., p53 mutations). These responses also include mechanisms that allow cells to tolerate and survive DNA damage.
Research in these related areas employs a broad range of approaches ranging from fundamental biochemical studies of purified proteins to cell biology to genetically engineered mouse models with impaired DNA damage response and repair pathways.