Metnase mediates chromosome decatenation in acute leukemia cells.
Metnase mediates chromosome decatenation in acute leukemia cells.
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DOI：
10.1182/blood-2008-08-175760
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发表时间：
2009-08
期刊：
影响因子：
20.3
通讯作者：
Justin W Wray;E. Williamson;S. Sheema;Suk-hee Lee;E. Libby;C. Willman;J. Nickoloff;R. Hromas
中科院分区：
文献类型：
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作者：
Justin W Wray;E. Williamson;S. Sheema;Suk-hee Lee;E. Libby;C. Willman;J. Nickoloff;R. Hromas
DNA 复制后，姐妹染色单体必须在有丝分裂前解开或连接，以便染色单体在后期不会撕裂。拓扑异构酶 IIalpha (Topo IIalpha) 是主要的去连接酶。 Topo IIalpha 抑制剂可防止细胞分裂，导致细胞在有丝分裂过程中停滞。在此，我们报道急性髓系白血病细胞无法在有丝分裂十级联检查点处停滞，并且它们通过该检查点的进展受到 DNA 修复成分 Metnase（也称为 SETMAR）的调节。 Metnase 含有 SET 组蛋白甲基化酶和转座酶核酸酶结构域，是非同源末端连接 DNA 双链断裂修复途径的组成部分。 Metnase 与 Topo IIalpha 相互作用并增强其去连接活性。在这里，我们表明，当去连接受到抑制时，多种类型的急性白血病细胞的有丝分裂停滞减弱，并且在急性髓系白血病（AML）细胞系中，这是由 Metnase 介导的。更重要的是，即使在临床 Topo IIalpha 抑制剂 VP-16 存在的情况下，Metnase 也允许这些 AML 细胞持续增殖。在体外，纯化的 Metnase 可防止 VP-16 对缠结 DNA 的 Topo IIalpha 串联作用的抑制。因此，Metnase 表达水平可以预测 AML 对 Topo IIalpha 抑制剂的耐药性，并且 Metnase 是小分子干扰的潜在治疗靶点。
After DNA replication, sister chromatids must be untangled, or decatenated, before mitosis so that chromatids do not tear during anaphase. Topoisomerase IIalpha (Topo IIalpha) is the major decatenating enzyme. Topo IIalpha inhibitors prevent decatenation, causing cells to arrest during mitosis. Here we report that acute myeloid leukemia cells fail to arrest at the mitotic decatenation checkpoint, and their progression through this checkpoint is regulated by the DNA repair component Metnase (also termed SETMAR). Metnase contains a SET histone methylase and transposase nuclease domain, and is a component of the nonhomologous end-joining DNA double-strand break repair pathway. Metnase interacts with Topo IIalpha and enhances its decatenation activity. Here we show that multiple types of acute leukemia cells have an attenuated mitotic arrest when decatenation is inhibited and that in an acute myeloid leukemia (AML) cell line this is mediated by Metnase. Of further importance, Metnase permits continued proliferation of these AML cells even in the presence of the clinical Topo IIalpha inhibitor VP-16. In vitro, purified Metnase prevents VP-16 inhibition of Topo IIalpha decatenation of tangled DNA. Thus, Metnase expression levels may predict AML resistance to Topo IIalpha inhibitors, and Metnase is a potential therapeutic target for small molecule interference.