Carcinogenesis, Vol 18, 2071-2076, Copyright © 1997 by Oxford University Press
IP Pogribny, L Muskhelishvili, BJ Miller and SJ James
Uracil can arise in DNA by misincorporation of dUTP into nascent DNA and/or
by cytosine deamination in established DNA. Based on recent findings, both
pathways appear to be promoted in the methyl-deficient model of
hepatocarcinogenesis. A chronic increase in the ratio dUTP:dTTP with
folate/methyl deficiency can result in a futile cycle of excision and
reiterative uracil misincorporation leading to premutagenic apyrimidinic
(AP) sites, DNA strand breaks, DNA fragmentation and apoptotic cell death.
The progressive accumulation of unmethylated cytosines with chronic methyl
deficiency will increase the potential for cytosine deamination to uracil
and further stress uracil mismatch repair mechanisms. Uracil is removed by
a highly specific uracil-DNA glycosylase (UDG) leaving an AP site that is
subsequently repaired by sequential action of AP endonuclease,
5'-phosphodiesterase, a DNA polymerase and DNA ligase. Since the DNA
polymerases cannot distinguish between dUTP and dTTP, an increase in
dUTP:dTTP ratio will promote uracil misincorporation during both DNA
replication and repair synthesis. The misincorporation of uracil for
thymine (5-methyluracil) may constitute a genetically significant form of
DNA hypomethylation distinct from cytosine hypomethylation. In the present
study a significant increase in the level of uracil in liver DNA as early
as 3 weeks after initiation of folate/methyl deficiency was accompanied by
parallel increases in DNA strand breaks, AP sites and increased levels of
AP endonuclease mRNA. In addition, uracil was also detected within the p53
gene sequence using UDG PCR techniques. Increased levels of uracil in DNA
implies that the capacity for uracil base excision repair is exceeded with
chronic folate/methyl deficiency. It is possible that enzyme-induced
extrahelical bases, AP sites and DNA strand breaks interact to negatively
affect the stability of the DNA helix and stress the structural limits of
permissible uracil base excision repair activity. Thus substitution of
uracil for thymine induces repair- related premutagenic lesions and a novel
form of DNA hypomethylation that may relate to tumor promotion in the
methyl-deficient model of hepatocarcinogenesis.
ARTICLES
Presence and consequence of uracil in preneoplastic DNA from folate/methyl-deficient rats
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock 72205, USA.
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