Thomas E Wilson, MD

Dr. Wilson received his MD PhD from Washington University in St. Louis in 1994, where he studied mechanisms of DNA binding by transcription factors. He continued at Washington University to complete residency training in Clinical Pathology, as well as a postdoctoral fellowship in DNA repair. Dr. Wilson joined the faculty in the Department of Pathology at the University of Michigan in 1999 as Assistant Professor and now holds the rank of Associate Professor. Dr. Wilson’s main areas of interest are basic research into molecular genetic mechanisms of DNA repair and associated mutagenesis in the germline and cancer genomes, in addition to being Associate Director of the Molecular Diagnostics Laboratory, which focuses on detection of clinically significant genetic alterations, and extensive educational involvement in teaching molecular genetics in several arenas. Dr. Wilson’s research interests are broad and address several connected themes. First, he uses yeast as a genetic model organism to study the basic in vivo repair mechanisms active at DNA double-strand breaks, especially nonhomologous end joining (NHEJ) , the pathway most associated with chromosomal rearrangements of the type detected in the clinic. This work focuses on understanding how NHEJ proteins interact with chromosome breaks to execute repair, and what factors cause repair to be accurate or inaccurate. Second, he uses mammalian cell systems to study the environmental and genetic influences on mechanisms of copy number variant (CNV) formation, an important and clinically relevant category of human genomic instability. This work focuses on the resolution of chromosome breaks created by replication stress. Finally, he is active in research connected to his graduate roots that applies nascent RNA sequencing to a variety of problems of the 4D nucleome, including the temporal and spatial relationships between repair, replication, and transcription. In all areas, Dr. Wilson’s group has a strong focus on practical applications of bioinformatics to microarrays and high-throughput sequencing data as used in experimental genetic science.

Molecular Diagnostics

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The goal of our laboratory is to gain insight into the molecular basis of chromosomal rearrangement in cancer and the germline by systematically identifying both enzymatic and structural components of the DNA double-strand break (DSB) repair mechanisms, and characterizing how these interact to achieve the sequence of events resulting in repair or rearrangement. This is done in part using novel assays developed in the genetically tractable model organism Saccharomyces cerevisiae, since it is clear that the fundamental mechanisms of DSB repair are preserved in all eukaryotes. Specific factors under study include non-homologous end joining (NHEJ) enzymes such as polymerases, nucleases and especially the critical DNA ligase IV. Questions center on the structural and biochemical features of these enzymes that allow them to uniquely participate in NHEJ, addressed using a combination of genetic and biochemical repair assays. Other factors of interest are the structural Ku and Mre11-Rad50 proteins. Here, questions center on the nature and assembly of the larger NHEJ repair complex, addressed using a combination of protein interaction and chromatin immunoprecipitation approaches. We finally are applying high-resolution and high-throughput genomic approaches to determine the impact of NHEJ and other nuclear factors on rearrangement potential. Our goal is to correlate yeast findings to genome stability in mammalian cells. This is being achieved by high-throughput genomic approaches in which spontaneous and induced structural changes of chromosomes are correlated to the status of the DSB repair machinery. These last efforts have led to a substantial bioinformatics focus that is additionally being extended to the study of transcriptional responses to DNA damage stress.