title: Can a Six-Letter Alphabet Increase the Likelihood of Photochemical Assault to the Genetic Code?
abstract: In 2014, two unnatural nucleosides, d5SICS and dNaM, were shown to selectively base pair and replicate with high fidelity in a modified strain of E. coli, thus effectively expanding its genetic alphabet from four to six letters. More recently, a significant reduction in cell proliferation was reported in cells cultured with d5SICS, and putatively with dNaM, upon exposure to brief periods of near-visible radiation. The photosensitizing properties of the lowest-energy excited triplet state of both d5SICS and dNaM were implicated in their cytotoxicity. Importantly, however, the excited-state mechanisms by which near-visible excitation populates the triplet states of d5SICS and dNaM are currently unknown. In this study, steady-state and time-resolved spectroscopies are combined with quantum-chemical calculations in order to reveal the excited-state relaxation mechanisms leading to efficient population of the triplet states in these unnatural nucleosides in solution. It is shown that excitation of d5SICS or dNaM with near-visible light leads overwhelmingly to ultrafast population of their triplet states on the femtosecond time scale. The results presented in this work lend strong support to the proposal that photoexcitation of these unnatural nucleosides can accelerate oxidatively generated damage to DNA and other biomolecules within the cellular environment.
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Brennan
authors.initials: B
authors.lastname: Ashwood
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, Cleveland, Ohio, 44106, USA.
authors.forename: Marvin
authors.identifier: http://orcid.org/0000-0002-9826-3225
authors.initials: M
authors.lastname: Pollum
authors.affiliation: Department of Chemistry and Center for Chemical Dynamics, Case Western Reserve University, Cleveland, Ohio, 44106, USA. cxc302@case.edu.
authors.forename: Carlos E
authors.identifier: http://orcid.org/0000-0002-3594-0890
authors.initials: CE
authors.lastname: Crespo-Hernández
mesh_terms: D020029:Base Pairing; D019295:Computational Biology; D004247:DNA / Q000737:chemistry*; D004261:DNA Replication / Q000235:genetics; D004926:Escherichia coli / Q000235:genetics*; D005815:Genetic Code; D005818:Genetic Engineering / Q000379:methods*; D008969:Molecular Sequence Data; D009711:Nucleotides / Q000737:chemistry*
chemical_list: D009711:Nucleotides; D004247:DNA
keywords: DNA damage; expanded genetic alphabet; femtochemistry; photochemistry; unnatural base pairs