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.
Shen
Wen Hong
WH
Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Balajee
Adayabalam S
AS
Wang
Jianli
J
Wu
Hong
H
Eng
Charis
C
Pandolfi
Pier Paolo
PP
Yin
Yuxin
Y
D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism*; D002503:Centromere / Q000378:metabolism; D043171:Chromosomal Instability; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D033481:Chromosomes, Mammalian / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D050687:E2F1 Transcription Factor / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology; D006801:Humans; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D051135:Rad51 Recombinase / Q000378:metabolism
D002868:Chromosomal Proteins, Non-Histone; D050687:E2F1 Transcription Factor; D050505:Mutant Proteins; C060905:centromere protein C; D051135:Rad51 Recombinase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C487757:Pten protein, mouse