Shen Wen Hong, Balajee Adayabalam S, Wang Jianli, Wu Hong, Eng Charis, Pandolfi Pier Paolo, Yin Yuxin
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Cell. 2007 Jan 12;128(1):157-70. doi: 10.1016/j.cell.2006.11.042.
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.
PTEN编码一种使P13 - K/AKT信号通路失活的脂质磷酸酶，该基因的广泛突变与原发性肿瘤相关。其中一些突变发生在磷酸酶结构域之外，这表明PTEN在肿瘤抑制中还有其他功能。我们报道了PTEN在控制染色体完整性方面的核功能。Pten基因的破坏会导致广泛的着丝粒断裂和染色体易位。PTEN定位于着丝粒，并与动粒的一个组成成分CENP - C存在物理关联。PTEN的C端突变体破坏了PTEN与着丝粒的关联，并导致着丝粒不稳定。此外，Pten基因缺失的细胞表现出自发性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着重要作用。我们认为PTEN是基因组完整性的守护者。
