Hartsuiker Edgar, Neale Matthew J, Carr Antony M
Genome Damage and Stability Centre, University of Sussex, Brighton BN19RQ, UK.
Mol Cell. 2009 Jan 16;33(1):117-23. doi: 10.1016/j.molcel.2008.11.021.
For a cancer cell to resist treatment with drugs that trap topoisomerases covalently on the DNA, the topoisomerase must be removed. In this study, we provide evidence that the Schizosaccharomyces pombe Rad32(Mre11) nuclease activity is involved in the removal of both Top2 from 5' DNA ends as well as Top1 from 3' ends in vivo. A ctp1(CtIP) deletion is defective for Top2 removal but overproficient for Top1 removal, suggesting that Ctp1(CtIP) plays distinct roles in removing topoisomerases from 5' and 3' DNA ends. Analysis of separation of function mutants suggests that MRN-dependent topoisomerase removal contributes significantly to resistance against topoisomerase-trapping drugs. This study has important implications for our understanding of the role of the MRN complex and CtIP in resistance of cells to a clinically important group of anticancer drugs.
为了使癌细胞对那些将拓扑异构酶共价捕获在DNA上的药物产生抗性，必须去除拓扑异构酶。在本研究中，我们提供证据表明，粟酒裂殖酵母Rad32（Mre11）核酸酶活性在体内参与从5' DNA末端去除Top2以及从3'末端去除Top1。ctp1（CtIP）缺失对于Top2的去除存在缺陷，但对于Top1的去除效率过高，这表明Ctp1（CtIP）在从5'和3' DNA末端去除拓扑异构酶方面发挥着不同的作用。对功能分离突变体的分析表明，依赖MRN的拓扑异构酶去除对抵抗拓扑异构酶捕获药物有显著贡献。这项研究对于我们理解MRN复合物和CtIP在细胞对一类临床上重要的抗癌药物的抗性中的作用具有重要意义。
