Not all interactions of chemicals and irradiation with DNA produce mutations. In fact, all cells
have efficient repair mechanisms that repair such lesions. DNA repair mechanisms include sets of
enzymes that survey DNA for specific kinds of damage, remove the altered portion ofDNA, and
then restore the correct nucleotide sequence. The important role of DNA repair in human
cancer has been established by the finding that a number of inherited defects in DNA repair systems
predispose individuals to getting cancer. These diseases include xeroderma pigmentosum,
ataxia telangiectasia, Fanconi’s anemia, Bloom’s syndrome, Cokayne’s syndrome, and hereditary
retinoblastoma. There are several types of DNA repair systems, a number of which have been preserved
from bacteria to humans. These include (1) abnormal precursor degradation, e.g., the hydrolysis of the oxidized nucleotide triphosphate 8-hydroxy-dGTP to its nucleotide 8-OHdGMP, preventing incorporation into DNA; (2) a visible light-activated photoreactivation repair mechanism for removal of UV-induced cyclobutane pyrimidine dimmers; (3) strand break repair via an action of DNA ligase, exonuclease,
and polymerase activities; (4) base excision repair that recognizes simple base alterations such
as cytosine deamination to uracil and requires the action of (a) a purine or pyrimidine glycosylase
that breaks the deoxyribose-base bond, (b) an endonuclease to cleave at the abasic site, (c) a phosphodiesterase to clip away the ‘‘naked’’ abasic site, (d) DNA polymerase, and (e) DNA
ligase to refill and reclose the site; (5) nucleotide excision repair that recognizes bulky DNA base
adducts, pyrimidine dimers, and base crosslinks and requires the concerted action of enzymes and recognition factors (see below); and (6) 06-alkyguanine-DNA alkyltransferase that recognizes and removes small alkyl adducts from DNA. In mammalian cells, key repair mechanisms are base excision repair, nucleotide excision repair, transcription-coupled repair, homologous recombination and end joining, and mismatch repair.
Excision repair is the most generalDNArepair mechanism in higher organisms. Base excision repair removes damage such as deaminated bases, oxidized or ring-opened bases generated by hydroxyl or superoxide radicals, and abnormally methylated bases such as 3-methyladenine.126 Nucleotide excision repair requires sequential steps of (1) preincision recognition of damage; (2) incision of the damaged DNA strand at or near the damaged site; (3) excision of the damaged site and local removal of nucleotides in both directions from the defect in the affected DNA strand; (4) repair replication to replace
the excised region, using the undamaged strand as a template; and (5) ligation to join the repaired
sequence of nucleotides at its 30 end to the contiguous DNA strand.125 DNA repair is usually very accurate, but if repair cannot occur prior to or during DNA replication it may be error prone. This errorprone, post-replication repair seems to be brought into play by certain types of agents or
when a cell is overwhelmed by damage that it cannot handle by excision repair before the cell
enters S phase during the next round of cell division. In this case, the new DNA is synthesized
on templates that still contain damaged bases, leading to mispairing or recombinational events that transfer damaged bases to daughter strands. For example, in mammalian cells, 5% to 30% of UV-induced thymidine dimers are transferred from parental to daughter strands during postreplication repair.129
Nucleotide excision repair (NER) of DNA in eukaryotic cells requires several gene products. Some of these gene products appear to be identical or highly homologous in yeast, rodents, and humans.130,131 A number of defects in the NER system have been found by studying mutations in cells from patients with xeroderma pigmentosum, in whom at least nine different kinds of mutations (i.e., nine different complementation groups) have been found.125 Some of these XP genes have been cloned and found to
be highly homologous to yeast RAD genes that are required for excision repair in Saccharomyces
cerevisiae.130–133 Some of the cloned human genes also correct repair defects in mutant rodent cells and are called excision repair crosscomplementing (ERCC) genes.
