Biology Reference
In-Depth Information
CHAPTER
3
Blockade of Base Excision Repair: Inhibition of
Small Lesions Results in Big Consequences to
Cancer Cells
Carlo Vascotto * , Melissa L. Fishel y
* University of Udine, Italy y Indiana University School of Medicine, Indianapolis, IN
INTRODUCTION
L ESIONS PROCESSED BY BE R
This chapter will focus on the base excision repair
(BER) pathway which is responsible for the repair of
single-base lesions and can be reconstituted in vitro
with a glycosylase, AP endonuclease, polymerase b ,
and a ligase. BER is the predominant pathway for the
repair of oxidative and alkylation DNA damage as
well as abasic or baseless sites. 1 Data from many
studies indicate that the coordination of the steps
within this pathway is essential to genomic integrity
and completion of repair. Without this balance of enzy-
matic activities, incomplete processing of the damage
occurs, repair intermediates accumulate, and eventu-
ally cells will die. Inhibition of proliferation and cell
death are desirable in tumor cell populations, therefore
inhibitors of BER proteins are under development and
currently being evaluated in the clinic. 2 e 3 Several of
these agents are being evaluated in combination with
numerous existing chemotherapeutic agents and radia-
tion therapy. Combination therapy with agents that
generate DNA damage that is repaired by BER is
reasonable and demonstrating efficacy both preclini-
cally and in early clinical trials. Inhibitors of BER
proteins have indications as single agents in tumor
with a reduced capacity for DNA repair (BRCA1/2
mutations) and in combination regimens. Perhaps
BER inhibitors could increase the therapeutic index
of currently used agents as well as play a role in
secondary treatments following acquired resistance to
traditional therapies.
DNA damage due to environmental factors and
normal metabolic processes inside the cell occurs at
a rate of 1,000 to 1,000,000 molecular lesions per cell
per day in humans. 4 The vast majority of DNA damage
affects the nature of the bases, which may be chemically
modified leading to the loss or corruption of the in-
formation held within the genome with potentially
deleterious effect for the cell. 4 Several DNA repair path-
ways exist to promptly repair damaged DNA, prevent-
ing genome instability and mutagenesis. Indeed,
genetic stability is threatened by the continuous expo-
sure of cellular DNA to various reactive species of
both exogenous and endogenous origins. 5 Exposure of
cells to exogenous reactive chemical agents, derived
from environmental sources or deliberately delivered
as chemotherapeutic drugs, may be directly responsible
for DNA base modification. 6 On the other hand, endog-
enous DNA damage is mainly due to the intrinsic insta-
bility of the DNA molecule and the exposure to reactive
metabolites that cause DNA oxidation, deamination,
and alkylation. 7 These modifications can affect the
ability of DNA bases to establish canonic Watson
e
Crick hydrogen-bonds, resulting in incorrect base
pairing and, as final consequence, in mutations that
affect fidelity during both gene transcription and DNA
replication processes. Base excision repair is the main
pathway for removing small, non-helix-distorting
base lesions from the genome, while the related nucleo-
tide excision repair (NER) pathway repairs bulky
 
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