PTEN stabilizes TOP2A and regulates the DNA decatenation.

Xi Kang,Kristy Lamb,Wen H. Shen,Jinxue He,Yuxin Yin,Ling Liang,Chang Song,Xiao Du,Cong Zhang,Yu Liu

doi:10.1038/srep17873

Xi Kang, Kristy Lamb + Show 8 more

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https://doi.org/10.1038/srep17873

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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.

Highlights

PTEN is a powerful tumor suppressor that antagonizes the cytoplasmic PI3K-AKT pathway and suppresses cellular proliferation
In order to determine whether PTEN is involved in the pre-mitotic regulation of chromosomal integrity, we stained for ultra-fine bridges (UFBs) with the SNF2 family helicase PICH31,36
We found that the number of PICH bridges increases in Pten−/− cells (Fig. 1a,b), indicating loss of PTEN contributes to errors in pre-mitosis chromatid organization

Summary

Introduction

PTEN is a powerful tumor suppressor that antagonizes the cytoplasmic PI3K-AKT pathway and suppresses cellular proliferation. 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. Recent data from our laboratory show that c-terminal PTEN deletion in mice leads to genomic instability and spontaneous formation of various tumors, including cancers and B cell lymphoma[12]. Insufficient resolution of replication generated DNA entanglements activates this checkpoint and delays entrance of cells into mitosis[22,24]. TOP2A functions in chromosome untangling and is essential for segregation of sister chromatids before anaphase[26] It is required for decatenation checkpoint activation[24,25].

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