PTEN stabilizes TOP2A and regulates the DNA decatenation

• Published in: Scientific reports 2015-12, Vol.5 (1), p.17873-17873, Article 17873
• Main Authors: Kang, Xi, Song, Chang, Du, Xiao, Zhang, Cong, Liu, Yu, Liang, Ling, He, Jinxue, Lamb, Kristy, Shen, Wen H., Yin, Yuxin
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/106; 13/109; 14; 14/32; 14/63; 42; 631/67/581; 631/80/103; 82; 82/1; 96; AKT protein; Anaphase; Animals; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Cell Cycle Checkpoints; Cell Line; Clonal deletion; Deoxyribonucleic acid; DNA; DNA - metabolism; DNA biosynthesis; DNA damage; DNA topoisomerase; DNA topoisomerase (ATP-hydrolysing); DNA Topoisomerases, Type II - genetics; DNA Topoisomerases, Type II - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Fibroblasts; G2 phase; Gene Expression Regulation; Gene Knockout Techniques; Humanities and Social Sciences; Humans; Mice; multidisciplinary; Mutation; Poly-ADP-Ribose Binding Proteins; Protein Binding; Protein Stability; PTEN Phosphohydrolase - deficiency; PTEN Phosphohydrolase - metabolism; PTEN protein; Science; Tumor suppressor genes; Ubiquitin - metabolism; Ubiquitin-Specific Proteases - metabolism; Ubiquitination
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep17873

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.