Critical steps in alkylation-induced aberration formation

The process leading to chromosomal aberrations as a consequence of DNA damage is probably best understood for simple alkylating agents. Various functions have been identified which are involved in the conversion of critical primary lesions to aberrations. O-6-methylguanine is considered to be an important critical preclastogenic DNA lesion, which is converted to aberrations in conjunction with faulty mismatch repair. It operates at sites of O-6-methylguanine-thymine mispairing, leading to not yet defined secondary lesions. It is proposed that these secondary lesions cause DNA replication inhibition, which triggers recombination (sister-chromatid exchange formation)and is a critical event involved in aberration production in the second post-treatment replication cycle. For N-alkylations, DNA replication inhibition may result from depurinations and base excision repair intermediates causing a block of replication. In consequence, sister-chromatid exchanges as well as chromosomal aberrations are formed in the first post-treatment replication cycle. Data are available to show that DNA replication inhibition and aberration production in the first post-treatment replication cycle are interrelated. (C) 1998 Elsevier Science B.V. All rights reserved.