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. O6-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 O6-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.
Kaina
B
B
Institute of Toxicology, Division of Applied Toxicology, Obere Zahlbacher Str. 67, D-55131 Mainz, Germany.
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D002453:Cell Cycle / Q000502:physiology; D002869:Chromosome Aberrations / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D005347:Fibroblasts; D006147:Guanine / Q000031:analogs & derivatives / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008770:Methylnitrosourea / Q000494:pharmacology; D051379:Mice; D009153:Mutagens / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D012854:Sister Chromatid Exchange / Q000187:drug effects
D000477:Alkylating Agents; D009153:Mutagens; D019384:Nucleic Acid Synthesis Inhibitors; D008769:Methylnitronitrosoguanidine; D006147:Guanine; D008770:Methylnitrosourea; C008449:O-(6)-methylguanine; D019853:O(6)-Methylguanine-DNA Methyltransferase