Essential role for nuclear PTEN in maintaining chromosomal integrity.
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.
Mesh Terms:
Animals, Cell Nucleus, Centromere, Chromosomal Instability, Chromosomal Proteins, Non-Histone, Chromosomes, Mammalian, DNA Breaks, Double-Stranded, DNA Repair, E2F1 Transcription Factor, Fibroblasts, Humans, Mice, Mutant Proteins, PTEN Phosphohydrolase, Protein Binding, Protein Transport, Rad51 Recombinase
Animals, Cell Nucleus, Centromere, Chromosomal Instability, Chromosomal Proteins, Non-Histone, Chromosomes, Mammalian, DNA Breaks, Double-Stranded, DNA Repair, E2F1 Transcription Factor, Fibroblasts, Humans, Mice, Mutant Proteins, PTEN Phosphohydrolase, Protein Binding, Protein Transport, Rad51 Recombinase
Cell
Date: Jan. 12, 2007
PubMed ID: 17218262
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