Chemistry Reference
In-Depth Information
displays selective affi nity for DNA modifi ed by cisplatin, but not for DNA modifi ed by
transplatin
70
and preferentially recognizes cisplatin-modifi ed DNA over oxaliplatin-
modifi ed DNA.
71
The hMutS
heterodimer recognizes the 1,2-GG intrastrand cross-
link of the cisplatin adduct, but it has no affi nity for the 1,3-GTG intrastrand
crosslink of transplatin.
72
The binding affi nity of hMutS
α
for the 1,2-GG intrastrand
crosslink of cisplatin is enhanced in duplexes containing a thymine incorporated
opposite the 5
α
guanine of the cross-link.
73,74
The data suggest that hMutS
′
or the 3
′
α
may interact with cellular platinum-DNA lesions (especially with intrastrand
crosslinks superimposed on a mismatch
73
) and infl uence the DNA repair and signal-
ling pathway, although a detailed mechanism of these processes is not known.
6.3.4 Binding of Proteins Involved in the Nonhomologous End-Joining System
DNA-PK is a core protein of the NHEJ pathway and binds to DNA modifi ed by
cisplatin. Its K80 subunit, which is responsible for the binding,
75
also has a high
affi nity to the major adduct of cisplatin, the 1,2-GG intrastrand crosslink, which is
only twofold lower than its affi nity to DNA ends.
76
DNA adducts of cisplatin do not
alter the ability of Ku to bind DNA ends, but do impair the translocation of Ku
proteins along DNA,
77
resulting in reduced affi nity of DNA-PKc to the Ku-DNA
complex, and reduced kinase activity.
78
6.3.5 Homologous Recombination Repair System
The Rad51-guided HRR system plays an important role in the recognition and
repair of DNA interstrand crosslinks. It is not unexpected that cells defi cient in the
HRR pathway become hypersensitive to cisplatin as well as to other interstrand
crosslinking agents. The repair of interstrand crosslinks has been shown to involve
components of the NER, HRR and TLS pathways.
79
However, the manner by which
HRR proteins specifi cally bind platinum adducts is unclear.
6.3.6 Processing of DNA Modifi ed by Antitumour Platinum Compounds by
Translesion Synthesis DNA Polymerases
Several TLS DNA polymerases (Table 6.2) bypass 1,2-GG intrastrand crosslinks of
cisplatin.
80 - 85
DNA polymerases that bypass cisplatin adducts
in vitro
include DNA
polymerases b,
m and h, whereas polymerases a ,
i ,
k and l are unable to perform
TLS past platinum adducts.
80,82,83,86
Each DNA polymerase displays a distinct spe-
cifi city in its lesion-bypass properties, including bypass ability, fi delity and extension
ability. For example, DNA polymerase h bypasses platinum adducts most effi ciently
in error - free TLS,
81,85
whereas polymerase m is the most error-prone enzyme. More-
over, two DNA polymerases often work together to complete TLS.
87
Although
polymerase z is unable to bypass certain DNA lesions, including those by platinum
agents, the enzyme has the ability to extend TLS once nucleotides are inserted
opposite DNA adducts by other polymerases.
88,89
Little is known about the TLS past
platinum interstrand crosslinks, although a single DNA polymerase is not likely to
