The structure of a DNA decamer containing a (6-4) adduct has been determined by NMR analysis.^69
Because (6-4) adducts are highly mutagenic and most often lead to a 3-T→C transition (85% replicating
error frequency), a DNA duplex was built having a mismatched base-pair for the 3-T residue with an
opposed G residue. The resulting NMR structure shows that normal Watson–Crick-type hydrogen bonding is
retained at the 5-T of the lesion site while the O-2-carbonyl of the 3-T residue forms hydrogen bonds
with the imino and amino protons of the opposed G residue. Hydrogen bonding thus stabilizes the overall
helix and restores the highly distorted conformation of the (6-4) adduct to the typical B-form-like DNA
structure (Figure 8.31b). This structural feature may thereby explain the marked preference for the inser-
tion of an A residue opposite the 5-T and a G residue opposite the 3-T of the (6-4) lesion during trans-
lesion synthesis, and so lead to the predominant 3-T→C transition.
Thomas Carell has undertaken a systematic analysis of how DNA sequence and duplex conformation
can influence the relative formation of these photochemical lesions.^70 It appears that the production of cis-
syncyclobutane photodimers from adjacent pyrimidines resulting from UVC irradiation is dramatically
inhibited in A-DNA and RNA conformations. The formation of pyrimidine photoproducts in B-DNA con-
formations is inhibited by the presence of flanking guanine residues.
The cyclobutane photodimers and the (6-4) photoproducts products can cause cell death, as based on
four criteria.
Dimers (80%) and (6-4) products (20%) are the major photoproducts at low doses.
Action spectra for the formation of both types of photoproduct correlate well with that for
cell death.
Enzymatic excision repair of both lesions enhances cell survival.
Cells deficient in excision repair are hypersensitive to the lethal effects of UV radiation.The formation of these types of lesion is responsible for the development of a large proportion of non-
melanoma skin cancers,71,72while the damage is limited by the action of many DNA repair enzymes
(Section 8.11). The mutagenic nature of cyclobutane dimers, (6-4) products and photohydrates is complex.^73
318 Chapter 8
Figure 8.31 (a) X-ray crystal structure of a DNA T<>T photoproduct within a duplex dodecamer
(Adapted from Ref. 68. © (2002), with permission from Elsevier)
(b) NMR structure of a DNA (4-6)Py photoproduct
(Adapted from Ref. 69. © (1995), with permission from Blackwell Publishing)