Essential role for nuclear PTEN in maintaining chromosomal integrity
Essential role for nuclear PTEN in maintaining chromosomal integrity
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DOI：
10.1016/j.cell.2006.11.042
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发表时间：
2007-01-12
期刊：
影响因子：
64.5
通讯作者：
Yin, Yuxin
中科院分区：
文献类型：
--
作者：
Shen, Wen Hong;Balajee, Adayabalam S.;Yin, Yuxin
PTEN编码一种可使P13-K/AKT途径失活的脂质磷酸酶，它的广泛突变与原发肿瘤有关。其中一些突变发生在磷酸酶结构域之外，这表明PTEN的额外活性在肿瘤抑制中发挥作用。我们报道了PTEN在控制染色体完整性中的核功能。Pten的破坏会导致着丝粒的广泛断裂和染色体易位。PTEN定位于着丝粒，并与CENP-C密切相关，CENP-C是着丝粒的一个组成部分。PTEN C端突变破坏了PTEN与着丝粒的结合，导致着丝粒不稳定。此外，Pten零细胞表现出自发的DNA双链断裂(DSB)。我们发现PTEN作用于染色质并调节RAD51的表达，从而降低自发性DSB的发生率。我们的结果表明，PTEN通过与着丝粒的物理相互作用和对DNA修复的控制，在维持染色体稳定性方面发挥了重要作用。我们认为PTEN是基因组完整性的守护者。
A broad spectrum of mutations in PTEN, encoding a lipid phosphatase that inactivates the P13-K/AKT pathway, is found associated with primary tumors. Some of these mutations occur outside the phosphatase domain, suggesting that additional activities of PTEN function in tumor suppression. We report a nuclear function for PTEN in controlling chromosomal integrity. Disruption of Pten leads to extensive centromere breakage and chromosomal translocations. PTEN was found localized at centromeres and physically associated with CENP-C, an integral component of the kinetochore. C-terminal PTEN mutants disrupt the association of PTEN with centromeres and cause centromeric instability. Furthermore, Pten null cells exhibit spontaneous DNA double-strand breaks (DSBs). We show that PTEN acts on chromatin and regulates expression of Rad51, which reduces the incidence of spontaneous DSBs. Our results demonstrate that PTEN plays a fundamental role in the maintenance of chromosomal stability through the physical interaction with centromeres and control of DNA repair. We propose that PTEN acts as a guardian of genome integrity.