The fission yeast Crb2/Chk1 pathway coordinates the DNA damage and spindle checkpoint in response to replication stress induced by topoisomerase I inhibitor
The fission yeast Crb2/Chk1 pathway coordinates the DNA damage and spindle checkpoint in response to replication stress induced by topoisomerase I inhibitor
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DOI：
10.1128/mcb.25.17.7889-7899.2005
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发表时间：
2005-09-01
影响因子：
5.3
通讯作者：
Francesconi, S
中科院分区：
文献类型：
--
作者：
Collura, A;Blaisonneau, J;Francesconi, S
生物体经历着不断挑战其基因组稳定性的威胁。当DNA受损时，DNA损伤检查点途径与DNA修复协调细胞周期进程，从而确保基因组的忠实传递。纺锤体组装检查点抑制染色体分离，直到所有染色体都正确地附着在纺锤体上，确保遗传物质的准确分割。DNA损伤和纺锤体检查点通路都参与基因组完整性。然而，这两种途径之间没有明确的联系。在这里，我们分析了介导Chk1激活的裂变酵母Crb2的BRCT结构域突变体，并为Chk1途径的新功能提供了证据。当Crb2突变体在抑制拓扑异构酶1的活性时经历了受损的复制分叉，Chk1。DNA损伤通路诱导纺锤体检查点的持续激活，从而以依赖于mad2的方式延迟中期到后期的转变。当细胞在缺乏熟练的G(2)/M DNA损伤检查点的情况下遭受复制应激时，这种新途径可提高细胞存活和基因组稳定性。
Living organisms experience constant threats that challenge their genome stability. The DNA damage checkpoint pathway coordinates cell cycle progression with DNA repair when DNA is damaged, thus ensuring faithful transmission of the genome. The spindle assembly checkpoint inhibits chromosome segregation until all chromosomes are properly attached to the spindle, ensuring accurate partition of the genetic material. Both the DNA damage and spindle checkpoint pathways participate in genome integrity. However, no clear connection between these two pathways has been described. Here, we analyze mutants in the BRCT domains of fission yeast Crb2, which mediates Chk1 activation, and provide evidence for a novel function of the Chk1 pathway. When the Crb2 mutants experience damaged replication forks upon inhibition of the religation activity of topoisomerase 1, the Chk1. DNA damage pathway induces sustained activation of the spindle checkpoint, which in turn delays metaphase-to-anaphase transition in a Mad2-dependent fashion. This new pathway enhances cell survival and genome stability when cells undergo replicative stress in the absence of a proficient G(2)/M DNA damage checkpoint.