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J. Biol. Chem., Vol. 266, Issue 3, 1469-1477, Jan, 1991
H Ide, LA Petrullo, Z Hatahet and SS Wallace
The processing of unrepaired DNA lesions is a key to understanding and
predicting the biological end points of particular DNA damages. In this
study, we prepared single-stranded f1 phage (f1-K12) DNA containing
dihydrothymine or beta-ureidoisobutyric acid as models for instructive or
noninstructive base lesions and assessed the potential biological
consequences of these lesions in vitro and in vivo. To determine the effect
of the two lesions on in vitro DNA synthesis, the extent of DNA synthesis
was measured by 3H-labeled nucleotide incorporation, and the newly
synthesized DNA was analyzed by DNA sequencing gels. The results showed
that dihydrothymine in the template was at most a weak block to in vitro
DNA synthesis catalyzed by Escherichia coli DNA polymerase I Klenow
fragment (Pol I) and T4 DNA polymerase. In contrast, beta- ureidoisobutyric
acid constituted a very strong (probably absolute) replicative block in
vitro. With Pol I, termination bands were observed either opposite or one
base prior to (3' to) the putative beta- ureidoisobutyric acid depending on
its position in the template. However, when DNA synthesis was catalyzed by
Pol I lacking a 3'----5' exonuclease activity, termination bands were only
observed opposite beta-ureidoisobutyric acid, with purine nucleotides being
incorporated preferentially opposite the lesion. With T4 DNA polymerase
that contains a very active 3'----5' exonuclease activity, DNA synthesis
was arrested almost exclusively one base prior to (3' to) the putative
beta- ureidoisobutyric acid site in the template. We also measured survival
of transfecting DNA containing dihydrothymine or beta-ureidoisobutyric acid
in an attempt to correlate the in vitro data with in vivo processing. In
keeping with the results obtained in vitro, dihydrothymine present in
transfecting f1-K12 DNA did not constitute an inactivating lesion. On the
other hand, it took 0.9 beta- ureidoisobutyric acid residues per molecule
to inactivate transfecting f1-K12 DNA, indicating that the lesion was an
absolute replicative block in vivo. When host cells were
ultraviolet-irradiated to induce the SOS response, a slight increase (about
2-fold) in survival of transfecting f1-K12 DNA containing
beta-ureidoisobutyric acid was observed. The potential effects of the
structures of base lesions on lesion-polymerase interactions are discussed.
Processing of DNA base damage by DNA polymerases. Dihydrothymine and beta-ureidoisobutyric acid as models for instructive and noninstructive lesions
Department of Microbiology and Molecular Genetics, University of Vermont, Burlington 05405.
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