Is FapyG mutagenic?: Evidence from the DFT study.
2,6-diamino-4-oxo-5-formamidopyrimidine (FapyG) is an oxidatively damaged product of guanine (G), which is mainly formed through metabolic processes that produce OH radicals. It has been proposed that in bacterial cells, FapyG retains the coding properties of G, and is, therefore, not mutagenic. However, in mammalian cells, FapyG induces G to thymine (T) mutation more dominantly than another ubiquitous oxidative lesion, that is, 8-oxoguanine (8-oxoG). The exact reasons for these coding properties of FapyG are not properly understood. In order to rationalize the cause of FapyG-mediated mutagenesis, all of the possible base-pair interactions of FapyG with cytosine (C), adenine (A), and T, in both anti- and syn- conformations, are studied in detail by using density functional theory (DFT). The effects of solvation on the coding properties of FapyG are also evaluated. We demonstrate that the anti-FapyG:C base pair has the highest binding energy, and that the base-pair alignment is similar to that of the normal G:C base pair. Therefore, insertion of C opposite anti-FapyG is preferred over the other DNA bases. This could be the reason for the non-mutagenic behavior of FapyG in bacterial cells. However, as the binding patterns and energies of anti-FpyG:A and syn-FapyG:A base pairs are similar, and these are also similar to those of the T:A base pair, mammalian polymerases may not distinguish between FapyG and T. As a result, A would be mistakenly inserted opposite either anti-FapyG or syn-FapyG, resulting in G to T transverse mutation.
Discipline of Natural Sciences, Indian Institute of Information Technology, Design and Manufacturing, Khamaria, Jabalpur-482005 (India); Current address School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane QLD 4072 (Australia). nrjena@iiitdmj.ac.in.
Nihar Ranjan
NR
Jena
Phool Chand
PC
Mishra
D000225:Adenine / Q000737:chemistry; D020029:Base Pairing; D003596:Cytosine / Q000737:chemistry; D004249:DNA Damage; D007536:Isomerism; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D016296:Mutagenesis; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity*; D013941:Thymine / Q000737:chemistry
D011743:Pyrimidines; C071023:2,6-diamino-4-hydroxy-5-formamidopyrimidine; D003596:Cytosine; D000225:Adenine; D013941:Thymine
DNA damage; cancer; density functional calculations; muagenesis; nucleobases