Nucleic Acids Research, Vol 25, Issue 6 1211-1218, Copyright © 1997 by Oxford University Press
GB Bauer and LF Povirk
Previous work showed that melphalan-induced mutations in the aprt gene of
CHO cells are primarily transversions and occur preferentially at G- G-C
sequences, which are potential sites for various bifunctional alkylations
involving guanine N-7. To identify the DNA lesion(s) which may be
responsible for these mutations, an end-labeled DNA duplex containing a
frequent site of melphalan-induced mutation in the aprt gene was treated
with melphalan, mechlorethamine or phosphoramide mustard. The sequence
specificity and kinetics of formation of both interstrand and intrastrand
crosslinks were determined. All mustards selectively formed two
base-staggered interstrand crosslinks between the 5'G and the G opposite C
in the 5'G-G-C sequence. Secondary alkylation was much slower for melphalan
than for the other mustards and the resulting crosslink was more stable.
Mechlorethamine and phosphoramide mustard induced intrastrand crosslinks
between the two contiguous Gs in the G-G-C sequence in double-stranded DNA,
but melphalan did not. Molecular dynamic simulations provided a structural
explanation for this difference, in that the monofunctionally bound
intermediates of mechlorethamine and phosphoramide mustard assumed
thermodynamically stable conformations with the second arm in a position
appropriate for intrastrand crosslink formation, while the corresponding
melphalan monoadduct did not.
ARTICLES
Specificity and kinetics of interstrand and intrastrand bifunctional alkylation by nitrogen mustards at a G-G-C sequence
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
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