PTEN stabilizes TOP2A and regulates the DNA decatenation.
PTEN stabilizes TOP2A and regulates the DNA decatenation.
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DOI：
10.1038/srep17873
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发表时间：
2015-12-10
影响因子：
4.6
通讯作者：
Yin Y
中科院分区：
文献类型：
--
作者：
Kang X;Song C;Du X;Zhang C;Liu Y;Liang L;He J;Lamb K;Shen WH;Yin Y
PTEN是一种强大的肿瘤抑制因子，其拮抗细胞质PI 3 K-AKT通路并抑制细胞增殖。PTEN还在维持细胞核中的基因组稳定性中发挥作用。在这里，我们报告说，PTEN促进DNA解链和控制一个解链检查点。DNA拓扑异构酶II（TOP 2）使复制过程中形成的DNA链解链，并且该过程由G2期的解链检查点主动监测。我们发现，PTEN缺陷的细胞在后期形成超细桥（UFB），这些桥是由于不充分的去连环化而产生的。我们表明，PTEN是物理上与脱连环酶TOP 2A和PTEN通过OTUD 3去泛素化酶影响其稳定性。在存在PTEN的情况下，TOP 2A的泛素化被OTUD 3抑制。PTEN的缺失或缺陷会导致TOP 2A的下调、去连环化检查点功能障碍以及G2和M期DNA去连环化不完全。我们认为，PTEN控制DNA去连环化，以维持基因组的稳定性和完整性。
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.