Biology Reference
In-Depth Information
CHAPTER
11
Apurinic/Apyrimindinic Endonuclease
in Redox Regulation and Oxidative Stress:
Implications for Regulation of DNA Repair
and T
herapeutic Develo
pment
Millie M. Georgiadis
Indiana University
Purdue University Indianapolis, Indiana University School of Medicine, Indianapolis, IN
e
INTRODUCTION
and the extracellular matrix; they convert superoxide into
H
2
O
2
and O
2
. Conversion of hydrogen peroxide to H
2
O
andO
2
is accomplishedby catalases and in a coupled reac-
tion by glutathione peroxidase with conversion of gluta-
thione (GSH) to its oxidized form (GSSG). Glutathione is
the most abundant peptide in cells and can also scavenge
ROS in a non-enzymatic process, as do other redox factors
such as thioredoxin, glutaredoxin, and peroxiredoxins.
2
General antioxidant molecules such as vitamins C and E
and beta carotene also scavenge reactive oxygen species.
3
Redox activemetals such as iron or copper also contribute
to reactive oxygen species. Fe(II) can react with H
2
O
2
producing the highly reactive hydroxyl radical through
the Fenton or Haber
An imbalance of the concentration of reactive oxygen
species (ROS) present and the ability of the cells to
neutralize ROS leads to oxidative stress. Oxidative stress
in turn can lead to aberrant signaling and/or genomic
instability, which may result in formation of tumors
(reviewed in
1
e
3
)(
Figure 11.1
). The level of ROS dictates
the cellular response, with high levels of reactive oxygen
species resulting in direct damage to the genome and
lower levels resulting in regulation of signaling path-
ways that may lead to genomic instability though induc-
tion of genes that cause tumorigenicity.
1
Accumulated
damage from ROS is also associated with aging, and
neurodegenerative diseases.
2,3
Although the mechanism
by which ROS induces tumor formation has yet to be
fully elucidated, a hallmark of tumors is elevated ROS,
and oxidative stress has historically been assumed to
contribute to tumor initiation and progression.
1
Reactive oxygen species include radical species super-
oxide (O2
-
) and hydroxyl radical (OH
) and the non-
radical species H
2
O
2
.
2
Superoxide results from a one
electron reduction of molecular oxygen and is produced
enzymatically by NADPH oxidases, cytochrome c
oxidase, and xanthine oxidase
2
and non-enzymatically
by leakage fromcomplex I and III of the electron transport
chain in mitochondria.
1
Exogenous sources of reactive
oxygen species include irradiation (UV, X-rays or
gamma-rays), atmospheric pollutants, and chemicals.
Superoxide dismutases are found in different cellular
compartments, including the cytoplasm, mitochondria,
mitochondrial intermembrane space, nucleus, lysosomes,
Weiss reaction. Microsomes and
preoxisomes are also sources of H
2
O
2
.
2
Conditions of oxidative stress when ROS levels are
elevated can lead to significant damage to macromole-
cules such as DNA, proteins, and lipids.
2
Of these, lipids
are most susceptible to oxidative modifications, but the
most significant threat to the cell results from oxidative
damage to genomic DNA, which can result in single-
and double-strand breaks. While proteins and lipids
are normally turned over in the cell, genomic DNA is
not. Thus, DNA damage must be repaired in order to
maintain genomic integrity. Damage to proteins results
in oxidative damage to a number of amino acid residues,
of which the most reactive is Cys. Oxidation of Cys resi-
dues leads to disulfide bonds or formation of sulfenic,
sulfinic or sulfonic acid, which normally inactivates
the protein, although in certain cases, oxidized proteins
are functional and in fact regulate response to oxidative
stress. Transcription factors that respond to oxidative
e
