Pommier Yves, Redon Christophe, Rao V Ashutosh, Seiler Jennifer A, Sordet Olivier, Takemura Haruyuki, Antony Smitha, Meng LingHua, Liao ZhiYong, Kohlhagen Glenda, Zhang HongLiang, Kohn Kurt W
Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute/NIH, Building 37, Room 5068, Bethesda, MD 20892-4255, USA.
Mutat Res. 2003 Nov 27;532(1-2):173-203. doi: 10.1016/j.mrfmmm.2003.08.016.
Topoisomerase I (Top1) catalyzes two transesterification reactions: single-strand DNA cleavage and religation that are normally coupled for the relaxation of DNA supercoiling in transcribing and replicating chromatin. A variety of endogenous DNA modifications, potent anticancer drugs and carcinogens uncouple these two reactions, resulting in the accumulation of Top1 cleavage complexes. Top1 cleavage complexes damage DNA and kill cells by generating replication-mediated DNA double-strand breaks (DSBs) and by stalling transcription complexes. The repair of Top1-mediated DNA lesions involves integrated pathways that are conserved from yeasts to humans. Top1-mediated DNA damage and cell cycle checkpoint responses can be studied biochemically and genetically in yeast and human cells with known genetic defects. Defects in these repair/checkpoint pathways, which promote tumor development, explain, at least in part, the selectivity of camptothecins and other Top1 inhibitors for cancer cells.
拓扑异构酶I（Top1）催化两个转酯反应：单链DNA切割和重新连接，这两个反应通常耦合以缓解转录和复制染色质中的DNA超螺旋。多种内源性DNA修饰、强效抗癌药物和致癌物会使这两个反应解偶联，导致Top1切割复合物的积累。Top1切割复合物通过产生复制介导的DNA双链断裂（DSB）和使转录复合物停滞来损伤DNA并杀死细胞。Top1介导的DNA损伤修复涉及从酵母到人类都保守的整合途径。在具有已知遗传缺陷的酵母和人类细胞中，可以通过生物化学和遗传学方法研究Top1介导的DNA损伤和细胞周期检查点反应。这些促进肿瘤发展的修复/检查点途径中的缺陷至少部分解释了喜树碱和其他Top1抑制剂对癌细胞的选择性。
