Claspin Inhibition Leads to Fragile Site Expression
Claspin Inhibition Leads to Fragile Site Expression
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DOI：
10.1002/gcc.20710
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发表时间：
2009-12-01
影响因子：
3.7
通讯作者：
Musio, Antonio
中科院分区：
文献类型：
--
作者：
Focarelli, Maria Luisa;Soza, Samuela;Musio, Antonio
脆性位点是姐妹染色单体交换、易位、缺失、复杂重排和基因扩增的热点。有人假设，脆弱部位的重排源于未复制区域，这些区域是由逃脱ATR复制检查点的失速叉子引起的。在本研究中，我们研究了编码ATR途径中的一种适配蛋白的Claspin(CLSPN)基因在人类细胞DNA复制应激中的作用。我们发现抑制CLSPN基因会导致基因组的不稳定和脆性位点的表达。在Aphidiclin处理后，我们发现由于Claspin需要检查点激活，所以Claspin合成一过性增加。然而，在长时间的aphidiclin治疗后，claspin的合成减少。我们认为，在极端复制阻断之后，CLSPN的调制允许罕见的细胞逃避检查点机制，进入有丝分裂，并伴随着基因组组装的缺陷。我们的观察结果为更好地理解细胞周期检查点在癌症中的去调节作用提供了基础。(C)2009年Wiley-Liss，Inc.
Fragile sites are hot spots for sister chromatid exchanges, translocations, deletions, complex rearrangements, and gene amplification. It has been hypothesized that rearrangements at fragile sites derive from unreplicated regions resulting from stalled forks that escape the ATR replication checkpoint. In the present study, we investigated the role of the Claspin (CLSPN) gene, which codes for an adaptor protein in the ATR pathway, during DNA replication stress in human cells. We show that the inhibition of the CLSPN gene leads to both genome instability and fragile site expression. Following aphidicolin treatment, we found a transient increase of Claspin synthesis due to its requirement to checkpoint activation. However, Claspin synthesis decreased after a prolonged aphidicolin treatment. We propose that CLSPN modulation, following an extreme replication block, allows rare cells to escape checkpoint mechanisms and enter mitosis with a defect in genome assembly. Our observations provide the basis for a better understanding of cell cycle checkpoints deregulation in cancer. (C) 2009 Wiley-Liss, Inc.