ABSTRACT
The human genome comprises three billion base pairs coding for 30,00040,000 genes. It is constantly under attack from endogenous mutagens, therapeutic drugs, and environmental stressors such as ionizing radiation, which threaten its integrity. Clearly the survival of the organism requires that the genome be under constant surveillance. This is accomplished by DNA repair mechanisms that have evolved to remove or tolerate precytotoxic, pre-mutagenic, and pre-clastogenic lesions in an error-free or sometimes error-prone way. Defects in DNA repair cause hypersensitivity to DNA-damaging agents, accumulation of mutations in the genome, and ultimately to the development of cancer and metabolic disorders. The importance of DNA repair to normal function is illustrated by the sporadic occurrence of the DNA repair deficiency syndromes that are characterized by increased cancer incidence and multiple metabolic disorders. There is an extensive array of enzyme systems in the cell, which can repair
damage to DNA. Two recent papers compiled data of 130 human DNA repair genes, which had been cloned and sequenced, although not all of them have been characterized as to their function [1,2]. DNA-repair genes can be subgrouped into genes associated with signaling and regulation of DNA repair and into genes associated with distinct repair mechanisms such as mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), direct damage reversal, and DNA double-strand break (DSB) repair. Some of these are specific for a particular type of damage (e.g., a particular base modification), while others can handle a range of different damages. These systems also differ in the fidelity of repair, which is in the degree to which they are able to restore the wild-type sequence. The eukaryotic cell has at least seven mechanisms to restore the structural
integrity of DNA:
. Direct repair of defects such as O6-alkylguanine formation
. NER, which fixes bulky lesions such as pyrimidine dimers produced by UV irradiation
. Base excision which repairs damaged bases and single-strand breaks (SSB)
. Mismatch repair which corrects mismatched nucleotides and small loops as they occur during replication
. Homologous recombination (HR) which repairs double-strand DNA breaks (DSBs)
. Nonhomologous end-joining (NHEJ) which repairs DSBs
. Poly(ADP-ribosyl) polymerase-1 (PARP) activity which, in conjunction with XRCC1 and ligase III, performs SSB repair and BCR.
