This web page was produced as an assignment for Genetics 564, an undergraduate capstone course at UW-Madison
Introduction
What is Chemical Genetics? [1,2]
Chemical Genetics is the process of examining the intersection between the genetic background of an organism and how different exogenous chemicals can perturb certain biological processes [1]. Like classical genetics, chemical genetics can be performed in a forward or reverse manner [2]. To understand what this means let's take examine the definitions in the context of classical genetics [2]. Researchers who take a forward classical genetics approach, are interested gene(s) that are involved in generating a known phenotype [2]. To do this researchers use a set of mutagens, often a chemical known as EMS, to introduce random mutations in the genome until an organism is found with the phenotype of interest [2]. The researcher can then examine what genes were altered to contribute to this phenotype [2]. In contrast, reverse classical genetics involves selecting a specific gene that is suspected to contribute to a phenotype of interest, mutating it, and then examining the effects of that specific mutation [2]. Similarly, these terms can be used in the context of chemical genetics [2]. Once again, for foward chemical genetic screens, a diverse set of small molecules can be applied to a wide variety of samples until the phenotype of interest is generated [2]. Once the phenotype of interest has been identified, the corresponding molecule that contributed to this phenotype can be found and studied in future research. Similarly, reverse chemical genetics focuses on an individual gene/protein, where a small, targeted set of molecules are applied to the protein of interest, and the phenotypic effects are assessed [2].
Results
Figure 1: 3D chemical structure of carboplatin a common molecule used to treat ovarian cancer
Figure 2: The ovarian steroid hormone estrogen, known for its mutagenic effects in HDR deficient cells.
Conclusions
Given the diversity of chemotherapy drugs and tumor inhibitors, as well as the large concentration of growth factors and steroid hormones present in the ovaries, a chemical genetic screen would be a valuable tool for identifying the effects of different steroid hormones on DNA repair. Since, we are interested in the role RAD51D plays in regulating DNA repair, one could use a reverse chemical genetic screen to test the effect of a targeted library against RAD51D. Perhaps ovarian hormones that are proliferative in nature will lead to the increased use of the deletion-prone single-strand annealing pathway, whereas other hormones, like progesterone do not significant alter DNA repair. Likewise, a large diversity of chemotherapy and anti-tumor medication can be used for a forward chemical genetic screen to see if the single stranded annealing pathway can be suppressed by exogenous drug treatments, leading to apoptosis of tumor cells.
References:
1. Nature. Chemical Genetics. Retrieved from https://www.nature.com/subjects/chemical-genetics.
2. Kawasumi M., Nghiem P. (2007). Chemical genetics: Elucidating biological systems with small-molecule compounds. Journal of Investigative Dermatology, 127 (7): 1577-1584. Retrieved from https://doi.org/10.1038/sj.jid.5700853
2. Kawasumi M., Nghiem P. (2007). Chemical genetics: Elucidating biological systems with small-molecule compounds. Journal of Investigative Dermatology, 127 (7): 1577-1584. Retrieved from https://doi.org/10.1038/sj.jid.5700853