Chemistry Reference
In-Depth Information
Table 6.3
Examples of human proteins involved in DNA repair that were shown to bind
specifi cally to DNA modifi ed by antitumour platinum compounds
Protein
Proposed function
Reference
3-methyladenine DNA glycosylase (AAG)
BER
97
XPA
NER
51
RPA
NER, HRR
51,53
XPC-HR23B
NER
60
RNA polymerase II
TC-NER
64-67
PARP-1
TC-NER
69
hMutS
α
(heterodimer of hMSH2 and hMSH6)
MMR
70,71
Ku80
NHEJ
76,78
SSRP1
Transcription elongation
95
ing a wide, shallow minor groove surface to which several classes of proteins bind.
The interstrand crosslink also induces several irregularities in DNA.
43
The crosslinked
guanine residues are not paired with hydrogen bonds to the complementary
cytosines, which are located outside the duplex. The
cis -
diammineplatinum(II)
bridge resides in the minor groove and the double helix is locally reversed to a left-
handed, Z-DNA-like form, markedly locally unwound and bent towards the minor
groove. The 1,3-GXG intrastrand crosslink formed by cisplatin locally unwinds and
bends the helix axis towards the major groove, but in contrast to 1,2-intrastrand
adducts, DNA is locally denatured and fl exible at the site of the 1,3-adduct.
44
The monofunctional adducts of cisplatin distort DNA in a sequence-dependent
manner.
45,46
These distortions disturb stacking interactions in double-helical DNA,
slightly unwind the duplex, but no intrinsic bending is induced by these adducts.
Direct analogues of cisplatin, such as carboplatin and oxaliplatin, produce adducts
similar to those produced by the parent drug, though different in their relative rates
of formation.
47 - 49
6.3.1 Base Excision Repair System
The human 3-methyladenine DNA glycosylase (AAG) is a BER enzyme that
removes a number of damaged bases from DNA, including adducts formed by some
chemotherapeutic agents. AAG readily recognizes cisplatin adducts, such as 1,2-GG,
1,2-AG and 1,3-GTG intrastrand crosslinks. 1,N-6-ethenoadenine, which is repaired
effi ciently by AAG, is recognized considerably more weakly than cisplatin adducts.
96
6.3.2 Nucleotide Excision Repair System
The NER proteins that exhibit enhanced affi nity to cisplatin-modifi ed DNA are
mainly those involved in the fi rst step in repair pathways, i.e. in damage recognition.
The repair proteins that probably have attracted the most attention are those that
are absent in patients suffering from the NER defi ciency characteristic of the disease
