The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning.
The ATP-dependent chromatin remodelling enzyme Uls1 prevents Topoisomerase II poisoning.
复制标题
ATP 依赖性染色质重塑酶 Uls1 可预防拓扑异构酶 II 中毒。
DOI：
10.1093/nar/gkz362
复制
发表时间：
2019
影响因子：
14.9
通讯作者：
Swanston A
中科院分区：
文献类型：
--
作者：
Swanston A
拓扑异构酶II （Top2）是一种重要的酶，通过瞬时的Top2-DNA共价中间体将DNA十烯酸盐化。这种中间体可以被一类称为Top2毒物的药物稳定，导致大量的DNA损伤。因此，Top2的活性是一把双刃剑，需要谨慎控制以保持基因组的稳定性。我们发现，一种三磷酸腺苷（ATP）依赖性染色质重塑（Snf2）酶Uls1可以改变酵母中Top2染色质的结合并防止Top2中毒。uls1的缺失突变体对Top2毒物吖啶黄（ACF）敏感，激活DNA损伤检查点。我们绘制了Uls1的Top2相互作用域，并表明这与其atp酶活性一起对Uls1的功能至关重要。通过执行ChIP-seq，我们发现ACF导致整个基因组中Top2结合的普遍增加。我们绘制了Uls1结合位点，并确定了tRNA基因作为ACF治疗后Uls1结合的关键区域。重要的是，Uls1在这些位点的存在阻止了acf依赖性Top2的积累。我们的数据揭示了Top2毒素对全球Top2结合格局的影响，并强调了Uls1在拮抗Top2功能中的作用。因此，重塑Top2结合是Snf2酶促进基因组稳定性的重要新手段。
Topoisomerase II (Top2) is an essential enzyme that decatenates DNA via a transient Top2-DNA covalent intermediate. This intermediate can be stabilized by a class of drugs termed Top2 poisons, resulting in massive DNA damage. Thus, Top2 activity is a double-edged sword that needs to be carefully controlled to maintain genome stability. We show that Uls1, an adenosine triphosphate (ATP)-dependent chromatin remodelling (Snf2) enzyme, can alter Top2 chromatin binding and prevent Top2 poisoning in yeast. Deletion mutants ofULS1are hypersensitive to the Top2 poison acriflavine (ACF), activating the DNA damage checkpoint. We map Uls1′s Top2 interaction domain and show that this, together with its ATPase activity, is essential for Uls1 function. By performing ChIP-seq, we show that ACF leads to a general increase in Top2 binding across the genome. We map Uls1 binding sites and identify tRNA genes as key regions where Uls1 associates after ACF treatment. Importantly, the presence of Uls1 at these sites prevents ACF-dependent Top2 accumulation. Our data reveal the effect of Top2 poisons on the global Top2 binding landscape and highlights the role of Uls1 in antagonizing Top2 function. Remodelling Top2 binding is thus an important new means by which Snf2 enzymes promote genome stability.