Chemistry Reference
In-Depth Information
be able to bypass this lesion. It has been suggested, however, that TLS may occur
during the repair of interstrand crosslinks.
79,90
Interestingly, polymerase h bypasses 1,2-GG crosslinks of oxaliplatin more
readily than 1,2-GG crosslinks of cisplatin.
91
This suggests that the conformations
of cisplatin- and oxaliplatin-GG adducts are different and that these conformational
differences have an infl uence on the ability of distantly related DNA polymerases
to perform translesion synthesis.
6.3.7 Binding of Other DNA Repair Proteins
The high - mobility - group (HMG) SSRP1 protein (structure - specifi c recognition
protein 1) is a member of a conserved chromatin-remodelling complex (FACT/
DUF/CP) implicated in DNA replication, basal and regulated transcription, and also
in DNA repair.
92,93
SSRP1 is the fi rst HMG-domain protein found to bind selectively
to DNA adducts of cisplatin.
94,95
The role of this protein in repair of DNA adducts
of platinum compounds is, however, unknown.
6.4 Repair of DNA Damage by Antitumour Platinum Compounds
6.4.1 Base excision Repair
The presence of cisplatin adducts in the reactions inhibits the excision of 1,N-6-
ethenoadenine by BER DNA glycosylase AAG. AAG readily recognizes cisplatin
intrastrand adducts while the 1,N-6-ethenoadenine adduct, which is repaired effi -
ciently by AAG, is recognized considerably more weakly. Despite the affi nity of
AAG for cisplatin adducts, AAG is unable to remove any of these adducts from
DNA. It has been suggested that cisplatin adducts could titrate AAG away from its
natural substrates, resulting in higher mutagenesis and/or cell death because of the
persistence of AAG substrates in DNA.
96
Another intriguing possibility is that AAG
binds to cisplatin adducts and, because it cannot remove them, it conveys the
adducts to the NER pathway through the interaction of AAG with the hHR23
proteins.
97
Thus the interaction between AAG and DNA adducts of cisplatin can
increase the effi ciency of DNA repair and, in the case of overexpression of this
protein, could lead to cisplatin resistance.
97,98
Hence, cisplatin may exhibit a syner-
gistic effect in potentiating the toxic effects of agents that are substrates for AAG.
6.4.2 Nucleoide Excision Repair
A major pathway used by human cells for the removal of platinum adducts from
DNA is NER. Typical experiments demonstrating NER of DNA adducts of plati-
num complexes were performed using linear DNA fragments of
150 base pairs
containing a platinum adduct in the centre of one strand. To allow for determination
of excision activity in human or rodent cell extracts, the modifi ed sequences con-
∼
