title: Reactivity of damaged pyrimidines: DNA cleavage via hemiaminal formation at the C4 positions of the saturated thymine of spore photoproduct and dihydrouridine.
abstract: Described here are mechanistic details of the chemical reactivities of two modified/saturated pyrimidine residues that represent naturally occurring forms of DNA damage: 5-thyminyl-5,6-dihydrothymine, commonly referred to as the "spore photoproduct" (SP), and 5,6-dihydro-2'-deoxyuridine (dHdU), formed via ionizing radiation damage to cytosine under anoxic conditions and also serving as a general model of saturated pyrimidine residues. It is shown that due to the loss of the pyrimidine C5-C6 double bond and consequent loss of ring aromaticity, the C4 position of both these saturated pyrimidines is prone to the formation of a hemiaminal intermediate via water addition. Water addition is facilitated by basic conditions; however, it also occurs at physiological pH at a slower rate. The hemiaminal species so-formed subsequently converts to a ring-opened hydrolysis product through cleavage of the pyrimidine N3-C4 bond. Further decomposition of this ring-opened product above physiological pH leads to DNA strand break formation. Taken together, these results suggest that once the aromaticity of a pyrimidine residue is lost, the C4 position becomes a "hot spot" for the formation of a tetrahedral intermediate, the decay of which triggers a cascade of elimination reactions that can under certain conditions convert a simple nucleobase modification into a DNA strand break.
authors.affiliation: Department of Chemistry and Chemical Biology, Indiana University-Purdue University Indianapolis (IUPUI) , 402 North Blackford Street, Indianapolis, Indiana 46202, United States.
authors.forename: Gengjie
authors.initials: G
authors.lastname: Lin
authors.forename: Yajun
authors.initials: Y
authors.lastname: Jian
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dria
authors.forename: Eric C
authors.initials: EC
authors.lastname: Long
authors.forename: Lei
authors.initials: L
authors.lastname: Li
mesh_terms: D053837:DNA Cleavage; D004249:DNA Damage; D003857:Deoxyuridine / Q000031:analogs & derivatives*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D011743:Pyrimidines / Q000737:chemistry*; D013941:Thymine / Q000031:analogs & derivatives* / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D011743:Pyrimidines; D014867:Water; C009484:5-thyminyl-5,6-dihydrothymine; D013941:Thymine; D003857:Deoxyuridine