The cellular genome is continually exposed to hazards that damage the DNA and reduce its stability, consequently triggering deleterious human health outcomes. Importantly, multiple enzymes involved in maintaining genomic stability are deregulated or mutated in cancer cells. While a general connection between DNA damage and human health has been established, it remains unclear how genome stability is altered at the molecular level. In this sense, the "devil is truly in the details" and gaining mechanistic insight is essential.
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The overarching goal of the lab is to fill the knowledge gap between DNA damage and human disease in hopes of beneficially impacting the treatment and/or prevention of human ailments. We are particularly interested in oxidative DNA damage because the basis of multiple human afflictions are rooted in oxidative stress. A primary defense mechanism employed during the repair of oxidative DNA damage is Base Excision Repair (BER). BER involves the removal of the damaged base and subsequent processing by a multi-protein complex that protects the cell from toxic DNA intermediates.
Major areas of research within the lab include:
Elucidating how DNA damage is generated, processed, and repaired
Identifying DNA polymerase strategies during replication and repair
Determining how large multi-protein complexes channel and protect toxic DNA intermediates during DNA damage processing
Utilizing creative structural techniques to probe key biological questions
Developing approaches to manipulate the DNA damage response to treat and prevent deleterious human diseases.
The lab utilizes a reductionist approach to investigate complex biological questions. This approach includes structural (x-ray and neutron), biochemical, kinetic, and molecular biology assays. The workhorse of the lab is x-ray crystallography. We have an in-house Rigaku MicroMax-007 HF rotating anode equipped with a Pilatus 200K detector that is utilized for the collection of publication quality macromolecular x-ray crystallographic data sets. We combine our multi-disciplinary approach with cellular collaborations to validate structure-function models.