Expanded Genetic DNA More Susceptible To Ultraviolet Light Damage

MedicalResearch.com Interview with:

Carlos E. Crespo-Hernández PhD Associate Professor and Co-director of the Center for Chemical Dynamics Department of Chemistry Case Western Reserve University Cleveland, Ohio

Dr. Carlos E. Crespo-Hernández

Carlos E. Crespo-Hernández PhD
Associate Professor and Co-director of the Center for Chemical Dynamics
Department of Chemistry
Case Western Reserve University
Cleveland, Ohio

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Two new letters of DNA have recently been successfully incorporated and replicated by a modified strain of E. coli, thus generating the world’s first semi-synthetic organism with an expanded genetic alphabet. With the expansion of the genetic alphabet, the question arises as to whether the incorporation of unnatural DNA base pairs into cells can adversely affect the integrity of the genetic code and the viability of the cells upon exposure to sunlight or even conventional laboratory lighting. Natural DNA is susceptible to damage by ultraviolet light, but this damage is largely repaired by enzymatic repair mechanisms in living cells. Our recent study has found that the two new, unnatural DNA bases—d5SICS and dNaM—are able to efficiently absorb near-visible light, which is abundant in sunlight and standard fluorescent lighting. Not only that, but upon absorbing near-visible light these unnatural bases produce up to 100 times more reactive species than the most reactive natural DNA base. A line of skin cancer cells incorporating one of these unnatural DNA bases was used to investigate these effects on living cells. Following exposure to a low dose of near-visible light, we observed an increase in the generation of reactive oxygen species within cells containing the unnatural DNA base and a significant decrease in cell survival.

MedicalResearch.com: What should readers take away from your report?

Response: The light-induced properties of unnatural DNA bases are commonly overlooked when they are used to expand the genetic code. This report shows that the photo-properties of these molecules can have damaging effects, which is likely exasperated by their close interaction with the replication machinery of cells. Scientists aiming at expanding the genetic alphabet using unnatural DNA bases should be mindful of the light-induced properties of these molecules or should at least protect the specimens from significant light exposure to avoid phototoxic side effects.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Currently, we know that these unnatural bases are highly photoreactive in solution and that they produce reactive oxygen species within cells and decrease cell survival upon exposure to near-visible light. However, the primary mechanism of phototoxicity, and whether these unnatural bases are incorporated into the DNA of natural cell lines or stay in the cytoplasm, are still unknown. Further investigations in these regards are required. Additionally, the light-induced properties of other unnatural DNA and RNA bases that are being developed to expand the genetic code of semi-synthetic organisms should also be investigated in order to guarantee their successful application and to know if measures need to be taken to protect them from light exposure.

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Unintended Consequences of Expanding the Genetic Alphabet
Marvin Pollum, Brennan Ashwood, Steffen Jockusch, Minh Lam, and Carlos E. Crespo-Hernández*
J. Am. Chem. Soc., 2016, 138 (36), pp 11457–11460
DOI: 10.1021/jacs.6b06822

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