Kaufmann W K
Department of Pathology, University of North Carolina at Chapel Hill, USA.
Cancer Metastasis Rev. 1995 Mar;14(1):31-41. doi: 10.1007/BF00690209.
Chemical carcinogenesis in the regenerating rat liver is cell-cycle-dependent. Proliferating hepatocytes were maximally susceptible to initiation by a single dose of benzo[a]pyrene diolepoxide I when at the G1/S border. Hepatocytes in early G1 or late S/G2/M were less susceptible and non-proliferating G0 hepatocytes were resistant to initiation. Radiation clastogenesis in proliferating human fibroblasts also is cell-cycle-dependent. Ultraviolet radiation (UV) induced maximal frequencies of chromosomal aberrations in synchronized cells that were at the G1/S border. Cells in early G1 or G2 were significantly less sensitive. For both initiation of chemical carcinogenesis and UV-clastogenesis, it appears that replication of damaged DNA is required and DNA repair before replication reduces cellular risk. If DNA repair is protective, cell cycle checkpoints which delay DNA replication and mitosis should augment this protective influence by providing more time for repair. The contribution of cell cycle checkpoint function to DNA repair during cell cycle-dependent clastogenesis was studied using ataxia telangiectasia (AT) fibroblasts. The AT cells displayed a defect in the coupling of DNA damage to checkpoints which control the G1/S and G2/M transitions and the rate of replicon initiation in S phase cells. UV-clastogenesis in AT cells was cell-cycle-dependent with irradiation at the G1/S boundary inducing 3-times more aberrations than treatment in G0 at the time of release into the cell cycle. Thus, DNA excision repair during the pre-replicative G1 phase was protective even in cells with defective checkpoint function. However, following irradiation at the G1/S border, AT cells displayed about 6-fold increased levels of UV-induced chromosome aberrations in comparison to normal human fibroblasts that were treated at this time. These observations indicate that secondary and tertiary DNA lesions that are produced during replication of UV-damaged DNA (replicative gaps and double-strand breaks) also depend on checkpoint function for repair. The replicon initiation and G2-delay checkpoints that operate after initiation of S phase appear to play a major role in protection against UV-clastogenesis.
再生大鼠肝脏中的化学致癌作用是细胞周期依赖性的。当处于G1/S边界时，增殖的肝细胞对单剂量苯并[a]芘二环氧物I的起始作用最为敏感。处于早期G1期或晚期S/G2/M期的肝细胞敏感性较低，而不增殖的G0期肝细胞对起始作用具有抗性。增殖的人成纤维细胞中的辐射断裂作用也是细胞周期依赖性的。紫外线（UV）在处于G1/S边界的同步化细胞中诱导出最高频率的染色体畸变。处于早期G1期或G2期的细胞敏感性明显较低。对于化学致癌作用的起始和UV断裂作用而言，似乎都需要损伤DNA的复制，并且复制前的DNA修复可降低细胞风险。如果DNA修复具有保护作用，那么延迟DNA复制和有丝分裂的细胞周期检查点应通过提供更多修复时间来增强这种保护作用。利用共济失调毛细血管扩张症（AT）成纤维细胞研究了细胞周期依赖性断裂作用期间细胞周期检查点功能对DNA修复的贡献。AT细胞在将DNA损伤与控制G1/S和G2/M转换以及S期细胞中复制子起始速率的检查点的偶联方面存在缺陷。AT细胞中的UV断裂作用是细胞周期依赖性的，在G1/S边界进行照射诱导的畸变比在释放到细胞周期时处于G0期时的处理多3倍。因此，即使在检查点功能有缺陷的细胞中，复制前G1期的DNA切除修复也是有保护作用的。然而，在G1/S边界进行照射后，与此时接受处理的正常人成纤维细胞相比，AT细胞中UV诱导的染色体畸变水平增加了约6倍。这些观察结果表明，在UV损伤DNA复制过程中产生的二级和三级DNA损伤（复制间隙和双链断裂）的修复也依赖于检查点功能。在S期起始后起作用的复制子起始和G2延迟检查点似乎在防止UV断裂作用方面起主要作用。
