Research Interests: Yanson Gu

My laboratory studies the mechanisms of DNA double strand break (DSB) repair, which have been implicated in the origin of chromosomal instability. DSB repair proteins also play an important role in the effectiveness of radiation treatment and some forms of chemotherapy that are designed to induce massive chromosome breaks that overwhelm the DNA repair capacity of cells and destroy tumors. However, it remains unclear how DNA repair defects may occur in individuals without inherited mutations in DNA repair genes, and how chromosomal instability evolves during tumor formation and progression. We employ genetic and molecular approaches to investigate the function of DNA repair genes.

One line of research is to investigate how Atm coordinates its signaling pathways with the Ku70-dependent DSB repair pathway in response to DSB ends. Mutations in the human ATM gene cause a chromosomal instability syndrome, Ataxia Telangiectasia. Our mouse model of this syndrome also recapitulates many developmental defects that are often inaccessible in human patients. Furthermore, the phenotypic characterization of both Atm and Ku70 mutant mice supports the notion that both proteins can sense DSB ends and activate independent repair/response pathways. In addition, we have genetic evidences implicating the potential cross-talk between these two proteins. We have designed experiments to determine whether and how gene silencing may be involved in the response to radiation, as well as in development, tumorigenesis and aging.

A second line of research is to investigate the specific role of chromosomal instability in both normal and malignant cell proliferation. We continue our investigation of the underlying mechanisms of DSB repair deficiency in our mouse models of chromosomal instability. To understand how these defects may lead to malignant transformation in different organs, we focus on the effect of chromosomal instability in several mouse models of carcinogenesis. This novel approach may help us to determine whether chromosomal instability can be used as a marker for staging tumor formation and progression. To facilitate this line of research, we are working with the UW Nuclear Imaging Group in order to apply imaging technology, such as positron emission tomography (PET), to study various mouse models of chromosomal instability.

The third research direction is to identify genetic variations in the estimated 200 human DNA repair genes, particularly those responsible for radiation sensitivity and tumorigenesis. We propose that such genetic variations may affect an individual's capacity to respond to and repair DNA damage. We have established a high throughput method to survey single nucleotide polymorphisms in the human population, and will test the significance of our finding in mouse models.