Biology Reference
In-Depth Information
with preferred and backup sub-pathways, and is linked to genome replication
and transcription. The early BER/SSBR enzymes, namely, DNA glycosylases
(DGs) and the end-processing proteins such as abasic endonuclease 1 (APE1),
form complexes with downstream repair (and other noncanonical) proteins via
pairwise interactions. Furthermore, a unique feature of mammalian early BER/
SSBR enzymes is the presence of a disordered terminal extension that is absent
in their
Escherichia coli
prototypes. These nonconserved segments usually
contain organelle-targeting signals, common interaction interfaces, and sites
of posttranslational modifications that may be involved in regulating their
repair function including lesion scanning. Finally, the linkage of BER/SSBR
deficiency to cancer, aging, and human neurodegenerative diseases, and ther-
apeutic targeting of BER/SSBR are discussed.
I. Oxidative DNA Damage and Its Repair in Mammalian Cells
The sequence fidelity of the genome, essential for maintaining phenotypes
of all organisms, is continuously challenged because of DNA's inherent insta-
bility, spontaneous chemical reactions, and replication errors. Moreover, all
aerobic organisms continuously generate reactive oxygen species (ROS) as by-
products of respiration. ROS are also produced by cellular oxidases in response
to a variety of external insults including environmental chemicals found in
cigarette smoke and chemotherapeutic drugs, ultraviolet (UV) light, or ionizing
radiation, and during inflammatory response.
1-4
Intracellular ROS include
superoxide anion (O
2
), the direct product of oxidases and respiration, while
hydroxyl radical (
OH) and hydrogen peroxide (H
2
O
2
) are generated via Fenton
reactions and enzymatic processes, respectively. The generated O
2
may be
scavenged by NO and form peroxynitrite (
OONO). Exogenous ROS includ-
ing singlet O
2
,O
3,
and
OH radical are produced during radiolysis of H
2
Oby
ionizing radiation. These reactive species produce multiple oxidative DNA
damage in aerobic organisms, including oxidized DNA bases, oxidized sugar
fragments, abasic (AP) sites, and single-strand breaks (SSBs). Furthermore,
closely spaced SSBs, oxidized bases, or abasic (AP) sites (generated during
repair) in the genome could form DNA double-strand breaks (DSBs). While
unrepairedDSBs are lethal, oxidized base lesions could bemutagenic, cytotoxic,
or both. Thus, ROS-induced genome damage represents the most pervasive
insult to the genetic material and more than 10
5
such lesions are estimated to be
generated by endogenous ROS in a mammalian cell per day.
3
Thus, it is not
surprising that ROS-induced genome damage has been implicated in a multi-
tude of diseases, including cardiovascular dysfunction, arthritis, and cancer, as
