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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage
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Yeast Tdp1 and Rad1-Rad10 function as redundant pathways for repairing Top1 replicative damage

机译：酵母Tdp1和Rad1-Rad10充当修复Top1复制损伤的冗余途径

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摘要

When a replication fork collides with a DNA topoisomerase I (Top1) cleavage complex, the covalently bound enzyme must be removed from the DNA 3' end before recombination-dependent replication restart. Here we report that the tyrosyl-DNA phosphodiesterase Tdp1 and the structure-specific endonuclease Rad1-Rad10 function as primary alternative pathways of Top1 repair in Saccharomyces cerevisiae. Thus, tdp1 rad1 cells (including the catalytic point mutant rad1-D869A) not only are highly sensitive to the Top1 poison camptothecin but also exhibit a TOP1-dependent growth delay. Extensive genetic analysis revealed that both Tdp1 and Rad1-Rad10 repair proceed through recombination that equally depends on RAD52, RAD51, and RAD50. The Rad1-Rad10 pathway further particularly depends on RAD59 and SRS2 but is independent of other nucleotide excision repair genes. Although this pattern is consistent with Rad1-Rad10 removing Top1 in a manner similar to its removal of nonhomologous tails during gene conversion, these differ in that Top1 removal does not require Msh2-Msh3. Finally, we show that yeast lacking the Rad1-Rad10-related proteins Mus81-Mms4 display a unique pattern of camptothecin sensitivity and suggest a concerted model for the action of these endonucleases.
机译：当复制叉与DNA拓扑异构酶I（Top1）切割复合物发生碰撞时，必须在重新启动依赖重组的复制之前将共价结合的酶从DNA 3'末端去除。在这里我们报告酪氨酸-DNA磷酸二酯酶Tdp1和结构特异性核酸内切酶Rad1-Rad10作为酿酒酵母Top1修复的主要替代途径。因此，tdp1 rad1细胞（包括催化点突变体rad1-D869A）不仅对Top1毒性喜树碱高度敏感，而且还表现出TOP1依赖性生长延迟。广泛的遗传分析显示，Tdp1和Rad1-Rad10修复均通过重组进行，重组同样取决于RAD52，RAD51和RAD50。 Rad1-Rad10途径还特别取决于RAD59和SRS2，但独立于其他核苷酸切除修复基因。尽管此模式与Rad1-Rad10以类似于在基因转换过程中去除非同源尾巴的方式去除Top1一致，但这些区别在于Top1去除不需要Msh2-Msh3。最后，我们表明缺乏Rad1-Rad10相关蛋白Mus81-Mms4的酵母显示喜树碱敏感性的独特模式，并建议这些核酸内切酶的行动的协调模式。

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