Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair
Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair
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DOI：
10.4161/cc.8.14.8947
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发表时间：
2009-07-15
期刊：
影响因子：
4.3
通讯作者：
Pandita, Tej K.
中科院分区：
文献类型：
--
作者：
Gupta, Arun;Yang, Qin;Pandita, Tej K.
PTEN缺陷细胞中的染色体显示出包括区域扩增在内的数量和结构改变。我们发现，PTEN缺陷的细胞显示正常的DNA损伤反应（DDR）证明了电离辐射（IR）诱导的磷酸化共济失调毛细血管扩张突变（ATM）以及其效应。PTEN缺陷细胞在辐射后Rad 51表达或DNA损伤修复动力学方面也没有缺陷。与此相反，咖啡因治疗，特别是增加IR诱导的染色体畸变和有丝分裂指数，只有在细胞与PTEN，而不是在细胞缺乏的PTEN，这表明他们的检查点是有缺陷的。此外，PTEN缺陷的细胞不能维持活跃的纺锤体检查点后，紫杉醇治疗。PTEN缺陷细胞中的基因组不稳定性不能归因于着丝粒处缺乏PTEN，因为在野生型细胞中没有检测到着丝粒DNA与PTEN之间的相互作用。这些结果表明，PTEN缺陷改变了多个细胞周期检查点，可能留下更少的时间用于DNA损伤修复和/或染色体分离，如在PTEN缺陷细胞中观察到的增加的结构以及数量改变所证明的。
Chromosomes in PTEN deficient cells display both numerical as well as structural alterations including regional amplification. We found that PTEN deficient cells displayed a normal DNA damage response (DDR) as evidenced by the ionizing radiation (IR)-induced phosphorylation of Ataxia Telangiectasia Mutated (ATM) as well as its effectors. PTEN deficient cells also had no defect in Rad51 expression or DNA damage repair kinetics post irradiation. In contrast, caffeine treatment specifically increased IR-induced chromosome aberrations and mitotic index only in cells with PTEN, and not in cells deficient for PTEN, suggesting that their checkpoints were defective. Furthermore, PTEN-deficient cells were unable to maintain active spindle checkpoint after taxol treatment. Genomic instability in PTEN deficient cells could not be attributed to lack of PTEN at centromeres, since no interaction was detected between centromeric DNA and PTEN in wild type cells. These results indicate that PTEN deficiency alters multiple cell cycle checkpoints possibly leaving less time for DNA damage repair and/or chromosome segregation as evidenced by the increased structural as well as numerical alterations seen in PTEN deficient cells.