Walter J. Chazin, Ph.D.

Integrative Structural Biology of Genome Maintenance and Innate Immunity

Research Keywords: DNA damage, DNA repair, DNA replication, fragment-based molecular discovery, inflammation, innate immune response, structural biology

Research Specialty: DNA replication, damage response and repair; innate immune and inflammatory response to pathogens

Research Description: The Chazin laboratory investigates the structural basis for recognition, biochemical function and biological specificity of proteins and nucleic acids. Specifically, we study systems involved in bacterial pathogenesis and cancer at the molecular level. Rather than focusing on specific techniques, we take a problem-oriented approach and use whichever techniques are necessary to answer the question at hand. This requires complementary application of a range of biophysical and structural approaches including NMR, crystallography, and electron microscopy. We also prioritize tight coupling of our research to functional analysis. This multi-disciplinary strategy is by nature very collaborative, which has stimulated our involvement in many multi-investigator projects.

Projects in the area of genome maintenance and cancer include understanding the translational potential of inhibition of nucleotide excision repair and elucidating mechanisms for replication fork remodeling. Projects in the area of innate immune response and inflammation in infectious disease include investigating the roles of calprotectin in nutritional immunity and in inflammation signaling via cell surface receptors.

Specific projects currently ongoing in the lab include:

1. Biochemical and Cryo-EM characterization of active multi-protein nucleotide excision repair (NER) machinery as it repairs damaged DNA.
2. Testing the hypothesis that defects in NER leads to increased sensitivity to Pt-based chemotherapeutics.
3. Fragment-based discovery of small molecular inhibitors of NER factor XPA.
4. Investigating the molecular basis for the negative regulation of RAD51 filaments by RADX and its role in replication fork stalling and reversal.
5. Generating a comprehensive mechanistic understanding of primer synthesis by polα–primase and the molecular basis for inhibitors.
6. Understanding the unique and varied roles of calprotectin in the innate immune response to pathogens termed nutritional immunity.
7. Defining the biochemical and structural mechanisms of bacterial zinc metallochaperones.

Significance of our genome maintenance research.  Life depends on maintaining the integrity of our genomes, which requires faithful replication and appropriate response and repair to aberrations in the DNA. We have wide ranging interest in all phases of genome maintenance but have increasingly focused on NER, bringing together our foundation in mechanism with the strong potential for translating our knowledge to the clinic. NER is the main pathway protecting genomes from DNA lesions formed by UV radiation and environmental mutagens. It is also crucial in cancer therapy because it repairs lesions formed by anticancer drugs, thereby contributing to chemoresistance. Understanding molecular mechanisms of NER has untapped potential in precision oncology and will inform efforts to develop novel anticancer therapeutics.

Significance of our innate immune response research:  Bacterial and viral pathogens are a significant threat to global public health and bacterial pathogens in particular have emerged as a leading cause of infection worldwide. The threat to public health is exacerbated by the growing resistance to current antibiotics. In fact, certain bacterial strains are resistant to all known antibiotics. It is therefore imperative to identify new therapeutic strategies and novel targets for the treatment of these infections. Our research is directed to a promising area of therapeutic development based on mimicking the potent nutritional immunity host defense against pathogens by exploiting the requirement for nutrient metals for pathogens to thrive and grow.

Postdoctoral Position Availability and Details: Postdoctoral positions are available for highly motivated biologists, biochemists, or structural biologists.  The Chazin laboratory uses integrative structural biology combined with biochemical and functional analysis with the goals of defining the mechanisms of action of cellular protein machinery, determining the relationship to disease, and evaluating potential targets for therapeutic intervention. These positions provide an excellent opportunity to become experienced in the integrated applications of advanced structural/dynamics and chemical biology methods at the cutting edge of genome maintenance or infectious disease medicine and biology. Applicants will work in multi-disciplinary teams with an extensive network of collaborators focused on fundamental biology and clinical applications, and will be encouraged to develop their leadership potential. The Chazin laboratory excels at fostering the achievements so that each group member achieves their full potential and attains their career objectives. To apply, send a cover letter and a CV to walter.chazin@vanderbilt.edu.

PubMed Listing of Dr. Chazin’s Publications