Chemical Genetics
This page was produced as an assignment for Genetics 564 an undergraduate capstone course at UW-Madison.
What is chemical genetics?
The cornerstone of chemical genetics is the use of small molecules to explore biological activity [1]. Chemical genetics relies on screens against microtiter plated chemical libraries to identify protein binding between the array of molecules in the library and the protein of interest. Chemical libraries come in two different flavors: focused libraries and diversity-oriented libraries. Figure 1 depicts the philosophical difference between these two different types of libraries. In focused libraries, similar small molecules are used as targets, providing a restricted analysis in terms of diversity of target binding, but a more specific analysis in terms of exact binding. In diversity-oriented libraries, a wide array of small molecules are used as targets, so the resulting analysis is overall more diverse but less specific.
In addition to analyzing protein binding, chemical libraries can be used to observe morphological traits, particularly in developing embryos. In one example, zebrafish embryos were placed in the plate wells and a screen against a variety of chemicals was performed, with the signal of interest being intersegmental vessel formation inhibition [2].
For the analysis of chemicals which may affect ERCC6, NCBI's PubChem database was used [3].
What chemicals affect ERCC6?
Searching for "Cockayne Syndrome" in the Bioassays search bar revealed no results. Searching for "ERCC6" in the Targets search bar also revealed no results. Searching for "ERCC6" in the Bioactivities search bar revealed 23 hits, all of which were siRNA or RNAi screens testing for results of inhibition on a particular process. There were not many results to choose from. However, it appears that at least some chemicals affect ERCC6:
Camptothecin is a chemical that is known to inhibit DNA topoisomerases. Camptothecin inhibits ligation after single-strand breaks. It also produces potentially lethal double-strand breaks when it encounters DNA replication machinery [4]. One study found that ERCC6 is inactivated by camptothecin [5].
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Doxorubicin, similar to camptothecin, is a topoisomerase inhibitor. Doxorubicin intercalates between base pairs in the DNA helix, which ultimately inhibits protein synthesis. In addition, the chemical has downstream effects that results in prevention of ligation after a double-strand break [6]. One study found that ERCC6 expression is inhibited by doxorubicin [7].
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Analysis
ERCC6 has at least two chemicals that in some way inhibit it's expression. Since both of the chemicals found inhibit DNA replication, it makes sense that ERCC6 would be inhibited. ERCC6 responds to DNA damage during replication, and if there is no replication taking place due to chemical inhibition, then ERCC6 will always be inhibited. These chemicals could be used to study the effects of ERCC6 loss in the regulation of oxidative damage.
References
[1] Stockwell, B. R. (2004). Exploring biology with small organic molecules. Nature, 432(7019), 846-854. http://doi.org/10.1038/nature03196
[2] Wang et al. (2010). Rosuvastatin, identified from a zebrafish chemical genetic screen for antiangiogenic compounds, suppresses the growth of prostate cancer. Eur Urol., 58(3), 418-426. doi: 10.1016/j.eururo.2010.05.024
[3] The PubChem Project. https://pubchem.ncbi.nlm.nih.gov/search/
[4] National Center for Biotechnology Information. PubChem Compound Database; CID=24360, https://pubchem.ncbi.nlm.nih.gov/compound/24360 (accessed Apr. 11, 2017).
[5] National Center for Biotechnology Information. PubChem BioAssay Database; AID=743121, https://pubchem.ncbi.nlm.nih.gov/bioassay/743121 (accessed Apr. 11, 2017).
[6] National Center for Biotechnology Information. PubChem Compound Database; CID=31703, https://pubchem.ncbi.nlm.nih.gov/compound/31703 (accessed Apr. 11, 2017).
[7] National Center for Biotechnology Information. PubChem BioAssay Database; AID=1053208, https://pubchem.ncbi.nlm.nih.gov/bioassay/1053208 (accessed Apr. 11, 2017).
Images and Videos
Cover image: http://www.emdmillipore.com/US/en/product/PCR-Cleanup-Filter-Plates,MM_NF-C7479?ReferrerURL=https%3A%2F%2Fwww.google.com%2F
Library image: http://pubs.rsc.org/en/content/articlelanding/2008/ob/b719372f#!divAbstract
This website was created for Genetics 564 by Zachary Beethem, an undergraduate genetics major at UW-Madison.
He can be reached via email: [email protected]
Date of last website update: April 2017
[1] Stockwell, B. R. (2004). Exploring biology with small organic molecules. Nature, 432(7019), 846-854. http://doi.org/10.1038/nature03196
[2] Wang et al. (2010). Rosuvastatin, identified from a zebrafish chemical genetic screen for antiangiogenic compounds, suppresses the growth of prostate cancer. Eur Urol., 58(3), 418-426. doi: 10.1016/j.eururo.2010.05.024
[3] The PubChem Project. https://pubchem.ncbi.nlm.nih.gov/search/
[4] National Center for Biotechnology Information. PubChem Compound Database; CID=24360, https://pubchem.ncbi.nlm.nih.gov/compound/24360 (accessed Apr. 11, 2017).
[5] National Center for Biotechnology Information. PubChem BioAssay Database; AID=743121, https://pubchem.ncbi.nlm.nih.gov/bioassay/743121 (accessed Apr. 11, 2017).
[6] National Center for Biotechnology Information. PubChem Compound Database; CID=31703, https://pubchem.ncbi.nlm.nih.gov/compound/31703 (accessed Apr. 11, 2017).
[7] National Center for Biotechnology Information. PubChem BioAssay Database; AID=1053208, https://pubchem.ncbi.nlm.nih.gov/bioassay/1053208 (accessed Apr. 11, 2017).
Images and Videos
Cover image: http://www.emdmillipore.com/US/en/product/PCR-Cleanup-Filter-Plates,MM_NF-C7479?ReferrerURL=https%3A%2F%2Fwww.google.com%2F
Library image: http://pubs.rsc.org/en/content/articlelanding/2008/ob/b719372f#!divAbstract
This website was created for Genetics 564 by Zachary Beethem, an undergraduate genetics major at UW-Madison.
He can be reached via email: [email protected]
Date of last website update: April 2017