Kaufmann W K
Department of Pathology, University of North Carolina, Chapel Hill 27599-7295.
Carcinogenesis. 1989 Jan;10(1):1-11. doi: 10.1093/carcin/10.1.1.
Mutagenesis, clastogenesis, and carcinogenesis, may all be S-phase dependent processes within carcinogen-damaged human cells. Carcinogens have been shown to inhibit replicative DNA synthesis in S phase cells and the mechanisms of inhibition have been identified. It is proposed that the sequelae of carcinogen action (mutations, sister-chromatid exchanges, chromosome aberrations) are the consequence of the production of lesions in the DNA template which interfere with the ability of DNA polymerase to synthesize a complementary strand without error. Mis-instructive lesions in the template give rise to base-substitution mutations in nascent strands as DNA polymerase inserts an incorrect but complementary base. Non-instructive base lesions and sterically interfering bulky adducts in the template inhibit DNA polymerase and cause the growing points of nascent DNA strands to be blocked. This blockage perpetuates discontinuities in daughter strands. These discontinuities are eliminated by a process known as post-replication repair. Blocked growing points may be relieved by un-directed insertion of DNA precursors to span the non-instructive lesions. Transient dislocation of the primer terminus from the damaged template may occur at palindromic or repetitive sequences. Reannealing of the primer terminus beyond the site of damage may allow bypass of blocking lesions with a consequence of deletion or insertion of genetic information. DNA at the site of blocked growing points may be a substrate for other enzymes involved in DNA metabolism. Single-strand gaps in daughter strands may be recognized by Rec A-like proteins which catalyze paranemic invasion of sister duplex strands. Recombination intermediates generated at sites of blocked growing points may be resolved by a pathway that produces either sister-chromatid exchanges or the insertion of a patch of parental template DNA within the daughter strand. Single-strand-specific endonuclease may attack regions of denatured DNA at blocked growing points producing double-strand breaks which appear to be intermediates in the formation of chromatid aberrations. The utilization of each of these pathways of post-replication repair will depend upon the precise structure of the template lesion, the sequence context in which the lesion is embedded in the template strand, and stochastic processes.
诱变、染色体断裂和致癌作用，可能都是致癌物损伤的人类细胞内依赖于S期的过程。致癌物已被证明会抑制S期细胞中的复制性DNA合成，并且抑制机制已经明确。有人提出，致癌物作用的后遗症（突变、姐妹染色单体交换、染色体畸变）是DNA模板中产生损伤的结果，这些损伤会干扰DNA聚合酶无误地合成互补链的能力。模板中的错误指导损伤会导致新生链中的碱基替换突变，因为DNA聚合酶会插入一个错误但互补的碱基。模板中的非指导碱基损伤和空间干扰性大分子加合物会抑制DNA聚合酶，并导致新生DNA链的生长点被阻断。这种阻断使子链中的不连续性永久存在。这些不连续性通过一种称为复制后修复的过程得以消除。受阻的生长点可能通过DNA前体的无定向插入来跨越非指导损伤而得到缓解。引物末端与受损模板的瞬时错位可能发生在回文或重复序列处。引物末端在损伤位点之外的重新退火可能允许绕过阻断损伤，其结果是遗传信息的缺失或插入。受阻生长点处的DNA可能是参与DNA代谢的其他酶的作用底物。子链中的单链缺口可能被类Rec A蛋白识别，这些蛋白催化姐妹双链的平行入侵。在受阻生长点处产生的重组中间体可能通过一条途径得到解决，该途径会产生姐妹染色单体交换或在子链内插入一段亲本模板DNA。单链特异性内切酶可能会攻击受阻生长点处的变性DNA区域，产生双链断裂，这些双链断裂似乎是染色单体畸变形成过程中的中间体。复制后修复的每种途径的利用将取决于模板损伤的精确结构、损伤在模板链中所处的序列背景以及随机过程。
