Brandt Eichman

Structural biology of DNA repair and replication machinery

Research in my laboratory is focused on understanding how proteins recognize and manipulate DNA structure to carry out various biological processes. We use X-ray crystallography to study the 3-dimensional atomic structures of proteins involved in DNA replication and repair.

Molecular mechanism of eukaryotic DNA replication initiation. The initiation of DNA replication in eukaryotic cells is a highly regulated process that is essential for maintenance of genome integrity. Failure to copy the genome only once and at the proper time during the cell cycle can lead to elevated mutation rates, chromosome instability, and the development of cancer. This process involves a choreographed assembly of several dynamic protein complexes which must recognize and unwind DNA at origins of replication, interpret cell cycle signals, and ultimately result in the formation of active replication forks. We are currently working to determine the crystal structures of several initiation proteins which are required for DNA unwinding and loading of DNA polymerases. Using a combination of structural, biophysical, biochemical, and biological approaches, we aim to generate a comprehensive model for the spatial arrangement of these proteins during DNA unwinding in an effort to understand the mechanism of replication initiation.

Enzymatic recognition and repair of damaged DNA. The stability of the genome is constantly challenged by the chemical reactivity of DNA bases, which are subject to modifications by cellular and environmental agents. These chemical modifications can cause DNA mutations or inhibit replication and thereby cause toxicity or disease. It is therefore important to understand the the basis for recognition of structural damage to DNA by repair proteins. DNA glycosylases locate and remove damaged bases from the DNA backbone and are specific to a particular type of modification. The importance of the substrate specificities of these enzymes is underscored by the fact that glycosylases must identify subtle changes in the DNA structure amidst a vast excess of unmodified DNA. We are studying the structural aspects of how DNA glycosylases recognize and remove alkylated bases from DNA.

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