The role of base excision repair in the repair of DNA adducts formed by a series of nitrogen mustard-containing analogues of distamycin of increasingbinding site size

Citation
N. Brooks et al., The role of base excision repair in the repair of DNA adducts formed by a series of nitrogen mustard-containing analogues of distamycin of increasingbinding site size, ANTI-CAN DR, 14(1), 1999, pp. 11-18
Citations number
32
Categorie Soggetti
Onconogenesis & Cancer Research
Journal title
ANTI-CANCER DRUG DESIGN
ISSN journal
02669536 → ACNP
Volume
14
Issue
1
Year of publication
1999
Pages
11 - 18
Database
ISI
SICI code
0266-9536(199902)14:1<11:TROBER>2.0.ZU;2-U
Abstract
The role of base excision repair in the repair of alkylation damage produce d by a series of sequence specific oligopyrrole-containing analogues of dis tamycin A that tether benzoic acid mustard (BAM) has been examined. Whereas BAM alkylates and cross-links in the major groove of DNA, attachment to py rrole units produces monoalkylations in the minor groove of DNA at AT tract s. Both sequence specificity of alkylation and cytotoxicity increase from o ne to three attached pyrrole units (compounds 1-3), and with 3 alkylation i s selective for purine-N3 in the sequence 5'-TTTTGPu (where Pu = guanine or adenine), In a model bacterial (Escherichia coli) system repair of the seq uence specific minor groove alkylations produced by 2 and 3 does not appear to involve BER, since neither a formamidopyrimidine-DNA glycosylase repair deficient E. coli mutant (BH 20, fpg(-) mutant) nor a 3-methyladenine-DNA glycosylase repair deficient mutant (GC 4803, tag(-)alkA(-) mutant) showed increased cytotoxicity to 2 or 3 compared with the wild type, AB 1157, The monopyrrole compound 1 was, however, similar to 4-fold more cytotoxic to th e GC 4803 mutant compared with wild type and BH 20, suggesting a role for t he 3-methyladenine-DNA glycosylase in the recognition and excision of the a dducts formed by 1. In contrast, increased sensitivity (>10-fold) was obser ved for the conventional nitrogen mustard BAM in the BH 20 strain, suggesti ng a role for the formamidopyrimidine-DNA glycosylase in the repair of the lesions produced by the agent. In a cell-free system the E. coli 3-methylad enine-DNA glycosylase (AlkA) was shown to remove alkylations at 5'-TTTTGPu sequences. However, the efficiency in removing the adducts formed by the ol igopyrrole compounds decreased dramatically from compound 1 to compound 3. Increasing the size of the DNA adduct formed in the minor groove therefore decreased the efficiency of recognition and removal of the adduct by the DN A glycosylase.