Chi Shin-Darlak, Ph.D.

Superfund Basic Research Program

Dr. Chi Shin-Darlak represents the prototypical SBRP student who is trained with the multidisciplinary perspective needed to follow the movement of toxicants from the environment to the cell, and then into the nucleus. Dr. Shin-Darlak entered her SBRP-funded training program with experience in bioremediation, but with no foundation on the cellular effects of environmental toxins. As a member of the SBRP team, she was exposed to research on the effects of toxins on both neuronal and non-neuronal cells types and became interested in how these agents can adversely affect the genome. For her graduate work, Dr. Shin-Darlak chose to look at how DNA damage translates into mutations. This triggered her interest in how chromatin (i.e., DNA and the proteins that coat it including histone) responds to environmental toxins and led directly to her choice of a research topic for a postdoctoral fellowship. Her research goal for when she establishes an independent laboratory is to study the impact of environmental toxins on cellular genomes.

Dr. Shin-Darlak began her work in environmental toxicology as a Masters level student at the University of Idaho where she studied soil biodegradation of 2,4,6-trinitrotoluene, a neurotoxic substance. She then entered the Environmental and Molecular Toxicology program at Oregon State University (Corvalis) and performed her Ph.D. work with Dr. Mitchell Turker. This work was supported by the Oregon Health & Science University (OHSU) SBRP training core and it allowed Dr. Shin-Darlak to learn the methods necessary to determine how environmental genotoxins interact with cellular genomes to induce mutations. Moreover, by taking advantage of DNA mismatch repair knockout mice available in the Turker laboratory, she demonstrated novel mutation patterns in genotoxin exposed DNA repair deficient cells. This work suggested that some damage-related mutational pathways are normally prevented by the action of DNA mismatch repair.

This figure shows a representative result from a mammalian reversion assay developed by Chi Shin-Darlak during her SBRP-supported graduate training. The stained colonies in the dish represent mouse cells carrying ultraviolet light-induced base-pair substitutions. The basic scheme for the reversion assay is to select mouse cells that have acquired APRT (adenine phosphoribosyltransferase) enzymatic activity due to a reversion mutation within mouse Aprt. In the example shown, codon 69 of mouse Aprt was mutated to inactivate the gene in such a way that either C→T or CC→TT mutations would restore enzymatic activity. Selective medium was then used to isolate the revertant cells and a sequence analysis used to determine the exact mutation that occurred. During her graduate training Chi generated a panel of cells to detect a variety of base-pair substitutions events in both DNA repair proficient and deficient backgrounds.

The next step towards her research career goal to focus on the dynamic process of chromatin remodeling and its role in DNA repair and mutation avoidance is to learn how to examine active and silenced chromatin. Dr. Shin-Darlak has accepted a joint postdoctoral fellowship in the laboratories of Drs. Marc Gartenberg and Danny Reinberg (University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School) who examine silenced chromatin in yeast and mammalian cells, respectively. Her first task as a postdoctoral fellow will be to adopt methods used to study chromatin in yeast to mammalian cells. She will then use these methods to study silencing in mammalian cells.

Though still training, Dr. Shin-Darlak has a clear history of success and a clear plan to build on this success to carve out an important niche for the study of the acute and chronic genomic effects that can result from environmental exposures.