title: Cell cycle checkpoint defects contribute to genomic instability in PTEN deficient cells independent of DNA DSB repair.
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.
authors.affiliation: Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Arun
authors.initials: A
authors.lastname: Gupta
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Raj K
authors.initials: RK
authors.lastname: Pandita
authors.forename: Clayton R
authors.initials: CR
authors.lastname: Hunt
authors.forename: Tao
authors.initials: T
authors.lastname: Xiang
authors.forename: Sandeep
authors.initials: S
authors.lastname: Misri
authors.forename: Sicong
authors.initials: S
authors.lastname: Zeng
authors.forename: Julia
authors.initials: J
authors.lastname: Pagan
authors.forename: Jessei
authors.initials: J
authors.lastname: Jeffery
authors.forename: Janusz
authors.initials: J
authors.lastname: Puc
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Feng
authors.forename: Simon N
authors.initials: SN
authors.lastname: Powell
authors.forename: Audesh
authors.initials: A
authors.lastname: Bhat
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yaguchi
authors.forename: Renu
authors.initials: R
authors.lastname: Wadhwa
authors.forename: Sunil C
authors.initials: SC
authors.lastname: Kaul
authors.forename: Ramon
authors.initials: R
authors.lastname: Parsons
authors.forename: Kum Kum
authors.initials: KK
authors.lastname: Khanna
authors.forename: Tej K
authors.initials: TK
authors.lastname: Pandita
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002869:Chromosome Aberrations; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D042822:Genomic Instability; D006801:Humans; D007259:Infrared Rays; D007621:Karyotyping; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D002110:Caffeine; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D051135:Rad51 Recombinase; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel