DNA is the genetic material for all organisms, and thus its integrity is maintained by extensive damage surveillance and repair mechanisms. On the other hand, DNA strands are constantly cut and rearranged in programmed fashions during numerous biological processes, including the generation of genetic and immunological diversities, resolution of topological problems in chromosomes, and the genome maintenance/repair pathways themselves. In addition, some viruses, such as HIV that causes AIDS, achieve infection by inserting viral DNA into the host's genomic DNA.
We are studying various DNA rearrangement systems relevant to human health including:
(1) Resolution of a concatenated DNA-replication intermediate into linear chromosomes in Borrelia burgdorferi , the Lyme disease spirochete
(2) Retroviral integration reaction in which the integrase protein encoded by HIV-1 and related retroviruses inserts viral DNA into the host's genome
We use x-ray crystallography as our primary tool to determine three-dimensional structures of the protein machineries that catalyze DNA strand cutting and rejoining reactions. The structural information helps us address mechanistic questions, namely how particular DNA sequences are recognized to initiate a DNA rearrangement reaction, how separate pieces of DNA are brought together and arranged for coordinated chemical reactions, and how reaction directionality is regulated. Better understanding of these aspects of the DNA rearrangement processes may ultimately aid in the design of new antibiotics and anti-viral drugs as well as the development of a sequence-specific gene delivery tool for safer gene therapy.
