Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair

Arun Gupta, Qin Yang, Raj K. Pandita, Clayton R. Hunt, Tao Xiang, Sandeep Misri, Sicong Zeng, Julia Pagan, Jessie Jeffery, Janusz Puc, Rakesh Kumar, Zhihui Feng, Simon N. Powell, Audesh Bhat, Tomoko Yaguchi, Renu Wadhwa, Sunil C. Kaul, Ramon Parsons, Kum Kum Khanna and Tej K. Pandita (2009) Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair. Cell Cycle, 8 14: 2198-2210. doi:10.4161/cc.8.14.8947


Author Arun Gupta
Qin Yang
Raj K. Pandita
Clayton R. Hunt
Tao Xiang
Sandeep Misri
Sicong Zeng
Julia Pagan
Jessie Jeffery
Janusz Puc
Rakesh Kumar
Zhihui Feng
Simon N. Powell
Audesh Bhat
Tomoko Yaguchi
Renu Wadhwa
Sunil C. Kaul
Ramon Parsons
Kum Kum Khanna
Tej K. Pandita
Title Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair
Formatted title
Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair
Journal name Cell Cycle   Check publisher's open access policy
ISSN 1538-4101
Publication date 2009-06-15
Year available 2009
Sub-type Article (original research)
DOI 10.4161/cc.8.14.8947
Volume 8
Issue 14
Start page 2198
End page 2210
Total pages 13
Editor Mikhail V Blagosklonny
Place of publication United States
Publisher Landes Bioscience
Collection year 2010
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
0601 Biochemistry and Cell Biology
Abstract 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.
Formatted abstract
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.

Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 30 Mar 2010, 16:12:56 EST by Amanda Jones on behalf of Medicine - Royal Brisbane and Women's Hospital