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Collateral Damage Occurs When Using Photosensitizer Probes to Detect or Modulate Nucleic Acid Modifications
Aaron M Fleming1, Michael B Chabot1, Ngoc L B Nguyen1
1Department of Chemistry, University of Utah, 315 S 1400 East, Salt Lake City, Ut84112-0850, USA.
Angewandte Chemie (International Ed. in English)
|December 17, 2021
Summary
Photosensitizers like riboflavin can oxidize DNA bases, but they are not selective. They react readily with guanine and even modified bases, limiting their use for targeted chemical biology.
Area of Science:
- Biochemistry
- Chemical Biology
- Molecular Biology
Background:
- Chemical modifications of nucleic acids are crucial for biological function.
- Photosensitizers such as riboflavin and anthraquinone were hypothesized to selectively oxidize modified DNA bases like N6-methyladenine (m6A) and 5-methylcytosine (5mdC).
Purpose of the Study:
- To investigate and rank the reactivity of photosensitizers (riboflavin, anthraquinone, Rose Bengal) with canonical and modified DNA nucleosides.
- To assess the chemoselectivity of these photosensitizers for potential applications in targeted nucleic acid modification.
Main Methods:
- Reactions of photosensitizers with canonical nucleosides (dA, dC, dG, dT) and modified nucleosides (5mdC, m6A, 8-oxoguanine (dOG), 8-oxoadenine (dOA)).
- Competition assays using single- and double-stranded DNA to compare the oxidation preference between guanine (dG) and modified bases (5mdC, m6A).
Main Results:
- 8-oxoguanine (dOG) was found to be the most reactive nucleoside towards the tested photosensitizers.
- Native guanine (dG) exhibited higher or similar reactivity compared to modified bases 5mdC and m6A.
- Competition experiments confirmed preferential oxidation of dG over 5mdC or m6A in DNA.
Conclusions:
- Photosensitizers act as indiscriminate oxidants of nucleic acids, demonstrating poor chemoselectivity.
- The lack of selectivity significantly hinders their application for targeted oxidation of specific modified nucleotides within cellular environments.
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