Inhibiting translesion DNA synthesis as an approach to combat drug resistance to DNA damaging agents
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Jung-Suk Choi1, Seol Kim2, Edward Motea3 and Anthony Berdis1,2,4,5
1Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA
2Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
3Departments of Radiation Oncology and Pharmacology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA
4Center for Gene Regulation in Health and Disease, Cleveland State University, Cleveland, OH 44115, USA
5Case Comprehensive Cancer Center, Cleveland, OH 44106, USA
Anthony Berdis, email: [email protected]
Keywords: DNA damage, DNA polymerization, chemotherapy, nucleoside analogs, leukemia
Received: February 24, 2017 Accepted: April 11, 2017 Published: April 19, 2017
Anti-cancer agents exert therapeutic effects by damaging DNA. Unfortunately, DNA polymerases can effectively replicate the formed DNA lesions to cause drug resistance and create more aggressive cancers. To understand this process at the cellular level, we developed an artificial nucleoside that visualizes the replication of damaged DNA to identify cells that acquire drug resistance through this mechanism. Visualization is achieved using "click" chemistry to covalently attach azide-containing fluorophores to the ethynyl group present on the nucleoside analog after its incorporation opposite damaged DNA. Flow cytometry and microscopy techniques demonstrate that the extent of nucleotide incorporation into genomic DNA is enhanced by treatment with DNA damaging agents. In addition, this nucleoside analog inhibits translesion DNA synthesis and synergizes the therapeutic activity of certain anti-cancer agents such as temozolomide. The combined diagnostic and therapeutic activities of this synthetic nucleoside analog represent a new paradigm in personalized medicine.
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