SOLUTION STRUCTURE OF THE AMINOFLUORENE-STACKED CONFORMER OF THE SYN [AF]-C-8-DG ADDUCT POSITIONED AT A TEMPLATE-PRIMER JUNCTION

Citation
B. Mao et al., SOLUTION STRUCTURE OF THE AMINOFLUORENE-STACKED CONFORMER OF THE SYN [AF]-C-8-DG ADDUCT POSITIONED AT A TEMPLATE-PRIMER JUNCTION, Biochemistry, 36(47), 1997, pp. 14491-14501
Citations number
34
Journal title
ISSN journal
00062960
Volume
36
Issue
47
Year of publication
1997
Pages
14491 - 14501
Database
ISI
SICI code
0006-2960(1997)36:47<14491:SSOTAC>2.0.ZU;2-V
Abstract
A solution structural study has been undertaken on the aminofluorene-C -8-dG ([AF]dG) adduct located at a single strand-double strand d(A1-A2 -C3-[AF]G4-C5-T6-A7-C8-C9-A10-T11-C12-C13) . d(G14-G15-A16-T17-G18-G19 -T20-A21-G22) 13/9-mer junction (designated [AF]dG 13/9-mer) using pro ton-proton distance and intensity restraints derived from NMR data in combination with a computational protocol, which includes intensity re finement. This single strand-double strand junction models one arm of a replication fork composed of a 13-mer template strand, which contain s the [AF]dG modification site, and a 9-mer primer strand, which has b een elongated up to, but not including, the modified guanine. The NMR data establish that the duplex segment retains a minimally perturbed B -DNA conformation including Watson-Crick hydrogen-bonding at the junct ional dC5.dG22 base pair. The NMR spectra are consistent with the guan ine ring of the [AF]dG4 adduct adopting a syn glycosidic torsion angle and being displaced into the major groove with the adjacent dC3 resid ue displaced into the minor groove. Such a base displacement of the mo dified guanine is accompanied by stacking of one face of the fluorene ring of [AF]dG4 with the dC5.dG22 base pair, while the other face of t he flourene ring is stacked with the purine ring of the nonadjacent dA 2 residue in the intensity-refined solution structures of the [AF]dG 1 3/9-mer. A comparison of structural features of the C-8-[AF]dG adduct (this study) with those of the (+)-trans-anti-N-2-[BP]dG adduct [Cosma n et al. (1995) Biochemistry 34, 15334-15350] in the same 13/9-mer jun ctional sequence context has identified common features associated wit h the alignment of the modified guanine adducts at the template-primer junction. Thus, despite differences in the covalent linkage site for the C-8-[AF]dG and (+)-trans-anti-N-2-[BP]dG adducts, one face of the aromatic ring of the carcinogen stacks over the junctional base pair a nd in so doing displaces the modified guanine in a syn alignment into the major groove. These results lend credence to earlier proposals tha t such an adduct alignment may represent a common mutagenic conformer at a template-primer junction associated with a replication fork.