Tazi J, Rossi F, Labourier E, Gallouzi I, Brunel C, Antoine E
Institut de Génétique Moléculaire de Montpellier, UMR 5535 CNRS, Université de Montpellier II, France.
J Mol Med (Berl). 1997 Nov-Dec;75(11-12):786-800. doi: 10.1007/s001090050168.
DNA topoisomerase I is required for the normal development of multicellular organisms, probably because it plays a role in controlling gene activity, in addition to its function in relieving tortional stress during DNA replication and transcription. The discovery of DNA topoisomerase I as a specific kinase that phosphorylates serine-arginine rich (SR) splicing factors may provide new insights into their precise function in regulating gene expression. It is clear that the splicing factors phosphorylated by DNA topoisomerase I can modulate gene expression by changing the splicing pattern of structural genes. Studies of the splicing mechanism suggest that the phosphorylation of serine residues of SR proteins contribute to their activity. As this phosphorylation can be accomplished by several kinases, it remains to be determined whether phosphorylation by DNA topoisomerase I protein kinase is the limiting step in regulating this process. The availability of specific inhibitors of DNA topoisomerase I, structurally related to the alkaloid camptothecin, have made it possible to address this question experimentally. These inhibitors, which hold great promise as antineoplastic drugs, lead to specific inhibition of SR protein phosphorylation in cultured cells. This observation will hopefully lead to improved understanding of the mechanism by which these drugs act at cellular level.
DNA拓扑异构酶I是多细胞生物正常发育所必需的，这可能是因为它除了在DNA复制和转录过程中缓解扭转应力的功能外，还在控制基因活性方面发挥作用。DNA拓扑异构酶I作为一种能使富含丝氨酸-精氨酸（SR）的剪接因子磷酸化的特异性激酶的发现，可能为其在调节基因表达中的精确功能提供新的见解。很明显，被DNA拓扑异构酶I磷酸化的剪接因子可以通过改变结构基因的剪接模式来调节基因表达。对剪接机制的研究表明，SR蛋白丝氨酸残基的磷酸化有助于其活性。由于这种磷酸化可由多种激酶完成，DNA拓扑异构酶I蛋白激酶的磷酸化是否是调节这一过程的限制步骤仍有待确定。与生物碱喜树碱结构相关的DNA拓扑异构酶I特异性抑制剂的出现，使得通过实验解决这个问题成为可能。这些抑制剂作为抗肿瘤药物具有很大的前景，它们能在培养细胞中特异性抑制SR蛋白的磷酸化。这一观察结果有望增进我们对这些药物在细胞水平上作用机制的理解。
