Biology Reference
In-Depth Information
FIGURE 11.1
A schematic representation is shown of sources and some of the cellular consequences of exposure to reactive oxygen species
(ROS). In response to elevated levels of ROS, cell signaling events can activate transcription factors, which in turn upregulate expression of DNA
repair proteins including apurinic/apyrinidimic endonuclease (APE1). In its capacity as a redox factor, APE1 reduces transcription factors
stimulating their DNA-binding activity. Other oxidized proteins are repaired by general redox systems, thioredoxin (TRX) and glutaredoxin
(GRX). E3330 inhibits the redox activity of APE1, blocking its ability to reduce oxidized transcription factors.
stress include AP-1 and NF-
k
B, and antioxidant respon-
sive elements found in the promoter regions of metallo-
thionein I, glutathione-S-transferase, and Mn
superoxide dismutase regulate expression of these genes
in response to oxidants.
3
More recently, p53 has also
been shown to play a role in cellular response to ROS
(reviewed in
4,5
). In a microarray analysis of H
2
O
2
treated cells, 16 of the 48 highly responsive genes were
identified as targets of p53.
4
Many of these genes are
antioxidants. Oxidative stress is also associated with
p53-dependent cell cycle arrest, DNA repair, and
apopotosis.
4
Damage to DNA in the form of oxidized bases is
repaired by the base excision repair pathway. A key
enzyme in BER, apurinic/apyrimidinic endonuclease
(APE1),
6
recognizes abasic sites produced either sponta-
neously or through removal of an oxidized base by
a DNA glycosylase. Knock-out of APE1 in mice is
embryonic lethal establishing APE1 as an essential
enzyme;
7
APE1 functions in base excision repair by
cleaving the phosphodiester backbone 5' of the abasic
site resulting in a 3'OH and 5' deoxyribose phosphate
(reviewed in
8
). Further processing by DNA polymerase
beta and DNA ligase completes the DNA repair. APE1 is
also a nuclear redox factor that recognizes oxidized tran-
scription factors and reduces them, significantly stimu-
lating their DNA-binding properties. In this regard,
APE1 plays a unique role in that it repairs both oxidized
DNA and a number of transcription factors, which in
turn regulate expression of DNA repair genes. Other
general redox systems, including thioredoxin and gluta-
redoxin systems, repair oxidized proteins through
reduction of disulfide bonds. Of particular importance
is the repair of transcription factors that are involved
in cellular response to oxidative stress. APE1 thus plays
an important role both in maintaining redox homeo-
stasis and repairing oxidative damage to DNA. Redox
regulation of DNA repair has been recently reviewed.
9
The focus of this chapter is the role of APE1 in redox
regulation and response to oxidative stress and recent
therapeutic developments targeting APE1's redox func-
tion (see
Figure 11.1
).
REDOX REGULATION
OF TRANSCRIPTION
All organisms from bacteria to man have systems in
place to respond to oxidative stress. Bacteria sense and
respond to oxidative stress in part through transcrip-
tional regulation. In Eschericia coli and Salmonella typhi-
murium, genes within the oxyR regulon are induced in
response to hydrogen peroxide.
10
This is one example
of redox regulation in which increasing concentrations
of hydrogen peroxide directly trigger a transcriptional
