Key Words: DNA damage and repair, genomic instability, gene targeting, DNA structure, cancer therapeutics
Our research efforts are focused in three general areas within an overall theme of genome instability, DNA damage and mechanisms of repair. A unique feature of our approach is an emphasis on the role of DNA structure, including non-canonical structures such as triplex DNA, as recognition sites for repair machinery, sources of genomic instability, and as a basis for technology to target DNA damage to specific genomic sites.
1. DNA structure in genomic instability and human disease.
The consequences of genomic instability are causative factors for several human diseases that involve repetitive DNA sequences. Many repetitive sequences are able to adopt non-B secondary structures. Interestingly, many of these repeats occur near breakpoints of chromosomal translocations, implicating them in cancer etiology. One example is the H-DNA-forming sequence in the human c-MYC gene that maps to breakage hotspots in Burkitt’s lymphoma, that we have discovered is both mutagenic and induces DNA double-strand breaks in mammalian cells. These exciting results provide the first evidence that naturally occurring H-DNA structures are mutagenic; they also support a role for DNA structure in oncogenic translocations. Our studies will determine the mutagenic potential and mechanistic role of non-canonical DNA structures in human disease, with an emphasis on translocation-mediated cancers
2. Molecular mechanisms of DNA damage recognition and repair.
Defects in DNA repair systems can lead to severe clinical disorders; for example, it is estimated that ~90% of human cancers result from improperly repaired DNA damage. Our work aims to elucidate the molecular basis of damage recognition in order to develop a better understanding of the mutagenic potential and cancer risks of different types of DNA lesions.
3. Novel strategies to modify gene structure and function in living organisms.
An area of intense investigation in my laboratory is the development of triplex technology to improve the existing gene targeting methods by directing damage to specific genomic sites to increase the frequency of recombination and to direct gene inactivation. Our objective is to improve the utility of triplex technology as a tool for genetic manipulation in animals and to develop novel therapeutic strategies for treating cancer.