The Dewar photoproduct of thymidylyl(3′→5′)- thymidine (Dewar product) exhibits mutagenic behavior in accordance with the “A rule”

Abstract

In contrast to the highly mutagenic pyrimidine(6 -4)pyrimidone photoproduct, its Dewar valence isomer (Dewar product) has low mutagenic potential and produces a broad range of mutations [LeClerc, J. E., Borden, A. & Lawrence, C. W. (1991) Proc. Natl. Acad. Sci. USA 88, 9685-9689]. To determine the origin of the mutagenic property of the Dewar product, we used experimental NMR restraints and molecular dynamics to determine the solution structure of a Dewar-lesion DNA decamer duplex. This DNA decamer duplex (DW͞GA duplex) contains a mismatched base pair between the 3 T residue of the Dewar lesion (T6) and an opposed G residue (G15). The 3 T (T6) of the Dewar lesion formed stable hydrogen bonds with the opposing G15 residue. However, the helical bending and unwinding angles of the DW͞GA duplex were much larger than those of a second duplex that contains the Dewar lesion and opposing A15 and A16 residues (DW͞AA duplex). The DW͞GA duplex showed poorer stacking interactions at the two bases of the Dewar product and at the adjacent A7⅐T14 base pair than did the DW͞AA duplex. These structural features imply that no thermal stability or conformational benefit is obtained by incorporating a G instead of an A opposite the 3 T of the Dewar lesion. These properties may thus facilitate the preferential incorporation of an A in accordance with the A rule during translesion replication and lead to the low frequency of 3 T3 C mutations observed at this site.I rradiation of DNA with UV light produces a variety of photoproducts that block DNA replication (1-6). When an SOS response is induced by UV irradiation, these photoproducts are bypassed with modest efficiency by DNA polymerase and give rise to mutations (5, 6). This process has been termed translesion replication (TR) or bypass synthesis, and mutations are caused by the tendency of DNA polymerase to insert an incorrect nucleotide opposite the lesion during TR (7,8).Although both the pyrimidine (6-4)pyrimidone photoproduct [(6-4) adduct], which is one of the major classes of UV-induced DNA photoproducts (9, 10), and its Dewar valence isomer (Dewar product) (Fig. 1A) cause mutations during TR, their mutagenic properties differ. The (6-4) adduct is highly mutagenic and yields a specific mutation (6,11,12). In SOS-induced Escherichia coli cells, the marked preference for the insertion of a guanine residue opposite the 3Ј T of (6-4) adducts during TR leads to a predominant 3Ј T3C transition with 85% replicating error frequency (6). In contrast, the Dewar product is less mutagenic and induces a broader range of mutations than does the (6-4) adduct (6, 12). In SOS-induced E. coli cells, adenine was found to be incorporated into the site opposite the 3Ј T of the Dewar product with a frequency of 72%, whereas G was incorporated only 21% of the time (6). Thus, the 3Ј T3C transition, which is the major class of mutations induced by the Dewar product, is produced with 13% replicating error frequency during TR (6).Enzyme repair rates of 49-residue oligonucleotides that contain site-spec...

The significance of the Dewar valence photoisomer as a UV radiation‐induced DNA photoproduct in marine microbial communities

“…The most striking result was the unambiguous detection of Dewar valence isomers in all samples, sometimes in amounts almost equal to that of 64PPs. DEWs have been extensively characterized from a chemical, structural and mutagenic point of view (Taylor and Cohrs, 1987;Taylor et al, 1990;Lemaire and Ruzsicska, 1993;Hwang et al, 1996;Smith et al, 1996;Lee et al, 2000). Yet, the actual detection of DEWs in cells has been limited, although a study in rodent cells allowed the authors to suggest that DEWs could play an important role in photobiology (Perdiz et al, 2000).…”

Molecular Mechanisms of Ultraviolet Radiation‐Induced DNA Damage and Repair

“…Hydrogen atoms are not shown, prepared from PDB entries 1TTD [24], 1CFL [25], and 1QKG [26] using PyMol. (version 1.1r1) [27].…”

Surviving the Sun: Repair and bypass of DNA UV lesions

“…The reduced base stacking and increased backbone flexibility around a UV lesion is evident in the atomic-resolution crystal structures as well as in silico and solution studies. [42][43][44] In the absence of any protein, a DNA decamer harboring a CPD is underwound and bent by 30 at the lesion. 42 The crosslinked bases of a thymine dimer are buckled relative to the adjacent bases [ Fig.…”