DNA Damage, Repair and Mutagenesis

.

Understanding DNA Damage is Crucial for the Study of Cancer

DNA is subjected to damage from many sources, including inescapable chemical reactions with oxygen and water. Other sources include ultraviolet radiation from the sun and chemicals that are present in the environment. If DNA is not properly repaired, cells will accumulate mutations, which can drive cancer development. Moreover, many cancer therapies cause DNA damage resulting in 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 working to understand:

  • 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 Goes 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.

Faculty Publications in this Research Area

  • The Polymerase Activity of Mammalian DNA Pol ζ Is Specifically Required for Cell and Embryonic Viability.  PLoS Genet. 2016
  • Phosphorylation-Dependent Enhancement of Rad53 Kinase Activity through the INO80 Chromatin Remodeling Complex. Mol Cell. 2015
  • Regulation of Mec1 kinase activity by the SWI/SNF chromatin remodeling complex. Genes Dev. 2015
  • Arginine methylation facilitates the recruitment of TOP3B to chromatin to prevent R loop accumulation. Mol Cell. 2014
  • Mouse tetrad analysis provides insights into recombination mechanisms and hotspot evolutionary dynamics. Nature Genet. 2014