title: PTEN stabilizes TOP2A and regulates the DNA decatenation.
abstract: PTEN is a powerful tumor suppressor that antagonizes the cytoplasmic PI3K-AKT pathway and suppresses cellular proliferation. PTEN also plays a role in the maintenance of genomic stability in the nucleus. Here we report that PTEN facilitates DNA decatenation and controls a decatenation checkpoint. Catenations of DNA formed during replication are decatenated by DNA topoisomerase II (TOP2), and this process is actively monitored by a decatenation checkpoint in G2 phase. We found that PTEN deficient cells form ultra-fine bridges (UFBs) during anaphase and these bridges are generated as a result of insufficient decatenation. We show that PTEN is physically associated with a decatenation enzyme TOP2A and that PTEN influences its stability through OTUD3 deubiquitinase. In the presence of PTEN, ubiquitination of TOP2A is inhibited by OTUD3. Deletion or deficiency of PTEN leads to down regulation of TOP2A, dysfunction of the decatenation checkpoint and incomplete DNA decatenation in G2 and M phases. We propose that PTEN controls DNA decatenation to maintain genomic stability and integrity.
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.|Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Kang
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Song
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Du
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Liang
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Jinxue
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Kristy
authors.initials: K
authors.lastname: Lamb
authors.affiliation: Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Wen H
authors.initials: WH
authors.lastname: Shen
authors.affiliation: Institute of Systems Biomedicine, Beijing Key Laboratory of Tumor Systems Biology, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.|Department of Radiation Oncology, Weill Medical College of Cornell University, New York, NY 10065, USA.|Peking-Tsinghua Center for Life Sciences, Beijing, 100191, China.
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Yin
mesh_terms: D000705:Anaphase; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002460:Cell Line; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000378:metabolism*; D000075223:Poly-ADP-Ribose Binding Proteins; D011485:Protein Binding; D055550:Protein Stability; D025801:Ubiquitin / Q000378:metabolism; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D025801:Ubiquitin; D004247:DNA; D051059:PTEN Phosphohydrolase; C000602831:OTUD3 protein, human; D064570:Ubiquitin-Specific Proteases; D004250:DNA Topoisomerases, Type II; C000618811:TOP2A protein, human; C000618812:Top2a protein, mouse