DNA repair in drug resistance: Studies on the repair process at the level of the gene

Abstract

Increasing evidence shows that DNA repair processes are important in drug resistance. In this article we will review some
types of DNA damage seen after chemotherapy and examine experimental results suggesting that enhanced DNA repair processes
can play a role in drug resistance. We will review aspects of the DNA repair mechanisms in mammalian cells, with an emphasis
on newer methodologies that allow us to study DNA damage and repair processes at the level of individual genes. It has recently
become possible to quantitate various types of damage in individual genes; this includes damage and repair after treatment
with cisplatin and alkylating agents, which are important drugs in anticancer therapy. Studies of this sort should broaden
our understanding of the mechanisms of drug resistance. It has been known for some time that DNA-damaging agents are distributed
heterogeneously in DNA, and it is now becoming apparent that DNA repair processes are also heterogeneous over the mammalian
genome. For instance, active genes are preferentially repaired, i.e., repaired faster or more efficient than noncoding genomic
regions and the bulk of the genome. Significant changes in the repair process at the level of important genes could be overlooked
if repair is only studied at the level of the overall genome, which represents an average of all repair events. When DNA repair
is increased in drug resistance, additional treatment with DNA repair inhibitors may render the chemotherapeutics more effective.
We will survey agents that affect the repair processes and enzymes that could represent targets for therapy in this situation.