Human chromosomes are constantly assaulted by challenges to their integrity as a result of either environmental agents that damage DNA or from normal DNA metabolism. The failure to repair damaged DNA faithfully is ultimately responsible for many human diseases, especially cancer. This laboratory focuses on the repair of 1 particular lesion in DNA, the double-strand break (DSB). DSBs arise from agents, such as ionizing radiation, and can also occur spontaneously during DNA replication. Our emphasis is on repair of DSBs by homologous recombination, with a particular interest in the role of homologous recombination in maintaining genetic stability. Understanding the repair of DSBs is not only important for basic science and health concerns, but also impacts on molecular genetic manipulations of mammalian genomes.

Homologous Recombination as a Major DNA Repair Pathway in Mammalian Cells

Homologous recombination has long been recognized as an important DSB repair pathway in model organisms, such as E. coli and yeast. By contrast, in mammalian cells, alternative nonhomologous processes were presumed to repair DSBs. We challenged this presumption by performing experiments in which we generated a single DSB in the genome of a mammalian cell line and then examined repair. These experiments conclusively demonstrated that homologous repair is a major repair pathway in mammalian cells.

Homologous recombination is stimulated in the range of 3 orders of magnitude by a break in the chromosome; and nearly half of the total repair events arise from homologous repair (Liang et al. Proc Natl Acad Sci USA. 1998). These experiments also confirmed an important role for nonhomologous repair, as had been predicted. We expect that use of the 2 pathways may differ in different cell types, depending on specific parameters (such as whether cells are cycling or resting).

Our long-term goals are to exploit the molecular genetic systems we have developed to understand the role of homologous recombination in maintaining genetic stability. We are determining factors that govern “partner choice” — i.e., the choice of which 2 DNA molecules recombine — as well as the protein components involved in the repair process. Meiotic (and germline) recombination is also a key interest, and we maintain a strong interest in developing technologies both to facilitate studies of DNA repair and to manipulate genomes. With these goals, we hope to contribute to the understanding of human disease, and potentially to its reversal, through genetic correction.