4 p.m. - 5 p.m. Location: SLC 1.102
Dr. Jason Slinker (UT Dallas)
Cancer treatments that exploit inherent differences in redox active enzymes to induce selective DNA damage represent a promising strategy for circumventing common therapeutic resistances. Challenges in attaining full understanding of the activity and lethality of these DNA damaging drugs involve controlling the pathways and cofactors present within the system and precisely understanding damage repair activity at the level of DNA. The Slinker Lab at UT Dallas has designed a chip platform of arrayed DNA modified electrodes that can be used to mimic the cellular environment and follow DNA repair activity. This approach enables selective management of biological cofactors and preservation of critical features of the cellular environment for real-time, selective study of repair activity, offering benefits over conventional alternatives such as gel shift, Western Blot, and comet assays. These devices were shown to sense damage-specific sensitivity thresholds on the order of femtomoles/nanograms of proteins with response times of seconds. These chips were subsequently implemented in the study of the anticancer agent beta-lapachone, which catalytically generates DNA damaging peroxide in the presence of overexpressed NAD(P)H:quinone oxidoreductase 1, a hallmark of many cancer cells. These electrochemical devices have shown real-time, selective response to drug-induced damage repair, demonstrating their utility in tracking environmental damage. Ongoing study will clarify the mechanism of selective cancer cell death induced by the DNA base-excision repair pathway.
Key to the operation of these devices is understanding the fundamental physics of DNA electronics—that is, how DNA can conduct electrons when attached to electrodes. Charge transport (CT) is understood to occur through the bases of DNA, but precisely how this can happen and what gives rise to differences when defects are present are not well understood. The Slinker group has created custom equipment for capturing the temperature-dependent properties of DNA CT under physiological conditions, important for maintaining the DNA base pairing and double helical structure. They have also developed software algorithms for efficiently extracting kinetic parameters from electrode-bound monolayers. The physics of DNA CT contributing to the implementation of biologically relevant sensors will be discussed.