Chemistry Reference
In-Depth Information
type of damage. Only a few types of DNA damage are repaired in this way, particu-
larly pyrimidine dimers resulting from exposure to ultraviolet (UV) light and
alkylated guanine residues that have been modifi ed by the addition of methyl or
ethyl groups at the O6 position of the purine ring. Enzymes that catalyse direct
repair reactions are widespread in both prokaryotes and eukaryotes, including
humans. This type of DNA repair has not been observed for DNA damaged by
antitumour metal - based drugs.
6.2.2 Excision Repair
Although direct repair is an effi cient way of dealing with particular types of DNA
damage, excision repair is a more general means of repairing a wide variety of
chemical alterations to DNA, including those induced by platinum antitumour
drugs. In excision repair, the damaged DNA is recognized and removed, either as
free bases or as nucleotides. The resulting gap is then fi lled in by synthesis of a new
DNA strand, using the undamaged complementary strand as a template. Three types
of excision repair - base-excision repair (BER), nucleotide-excision repair (NER)
and mismatch repair (MMR) - enable cells to cope with a variety of different kinds
of DNA damage.
Base Excision Repair
Common small lesions, especially methylated or oxidized bases, or uracil in DNA
resulting from spontaneous deamination of cytosine are corrected by this type of
DNA repair. An altered base is specifi cally recognized by one of many specialized
glycosylases. The recognition process may be sensitive to enhanced DNA fl exibility
or to decreased base-pair stability as well as to steric effects like protrusions in the
grooves. The glycosylase removes the offending base, giving an abasic site or AP site
(apurinic/apyrimidinic site). The common feature of the glycosylases is that they
tend to fl ip out the base and do chemistry on the extrahelical base. Excision of a
damaged base and subsequent processing of the resulting single-strand break lead
to an intermediate, containing a 3
-hydroxyl, suitable for priming strand resynthesis
by a polymerase (Table 6.2). The majority of BER proceeds through the so-called
'short-patch' subpathway in which a single nucleotide is removed and replaced. In
this pathway (Figure 6.1), DNA resynthesis is carried out by polymerase b (Table
6.2), a member of the X family of polymerases (this DNA polymerase has the unique
ability to repair single-stranded DNA gaps smaller than six nucleotides; it fi lls single
nucleotide gaps in DNA produced by the BER pathway of mammalian cells).
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DNA ligase I or III completes the repair by sealing DNA ends.
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′
Nucleotide Excision Repair
In NER a small region of the strand surrounding the damage is removed from DNA
as an oligonucleotide. The small gap left in the DNA helix is fi lled by the sequential
action of DNA polymerase and DNA ligase. NER is generally thought of as a repair
system for bulky adducts, that recognizes a wide range of substrates, such as damage
caused by UV irradiation and chemical agents, including platinum anticancer drugs.
