Heilbronn R, Schlehofer J R, Yalkinoglu A O, Zur Hausen H
Int J Cancer. 1985 Jul 15;36(1):85-91. doi: 10.1002/ijc.2910360114.
Inhibitors of DNA polymerase alpha (aphidicolin, phosphonoacetic acid, phosphonoformic acid) efficiently inhibit initiator-induced amplification of SV40 DNA sequences in the SV40-transformed Chinese hamster cell line CO631. Amplification is also inhibited by various protease inhibitors (antipain, leupeptin, aprotinin, alpha-I-antitrypsin, epsilon-amino-caproic acid, soy-bean protease inhibitor), by the non-initiating but DNA-damaging agent caffeine, and by sodium butyrate, which inhibits DNA synthesis by histone modification. In contrast, an inhibitor of topoisomerase II, nalidixic acid, enhances amplification when applied simultaneously with initiating treatment. This latter compound does not induce amplification when applied without initiator. Cycloheximide induces DNA amplification in the same way as chemical and physical carcinogens. This amplification can still be observed when protein synthesis is completely blocked. The data suggest a complex mechanism of selective DNA amplification. The possible involvement of proteases leading to a functional modification of DNA polymerase alpha is discussed.
DNA聚合酶α的抑制剂（阿非迪霉素、膦乙酸、膦甲酸）能有效抑制SV40转化的中国仓鼠细胞系CO631中引发剂诱导的SV40 DNA序列扩增。各种蛋白酶抑制剂（抗蛋白酶、亮抑蛋白酶肽、抑肽酶、α-1抗胰蛋白酶、ε-氨基己酸、大豆蛋白酶抑制剂）、非引发性但能损伤DNA的咖啡因以及通过组蛋白修饰抑制DNA合成的丁酸钠也能抑制扩增。相比之下，拓扑异构酶II的抑制剂萘啶酸在与引发处理同时应用时会增强扩增。后一种化合物在无引发剂时应用不会诱导扩增。环己酰亚胺与化学和物理致癌物一样能诱导DNA扩增。当蛋白质合成完全被阻断时仍能观察到这种扩增。数据表明存在一种复杂的选择性DNA扩增机制。文中讨论了蛋白酶可能参与导致DNA聚合酶α功能修饰的情况。
