Topoisomerase IIα Is Required for Embryonic Development and Liver Regeneration in Zebrafish
Topoisomerase IIα Is Required for Embryonic Development and Liver Regeneration in Zebrafish
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DOI：
10.1128/mcb.01684-08
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发表时间：
2009-07-01
影响因子：
5.3
通讯作者：
Zon, Leonard I.
中科院分区：
文献类型：
--
作者：
Dovey, Michael;Patton, E. Elizabeth;Zon, Leonard I.
拓扑异构酶解决了DNA在整个细胞生命周期中遇到的拓扑问题。拓扑异构酶II α在真核生物中高度保守，在有丝分裂期间解开复制的染色体，并且是细胞活力绝对必需的。一个纯合的致死突变体，can4，被确定在一个屏幕上，以确定重要的基因细胞增殖在斑马鱼通过利用抗体对有丝分裂特异性标记，磷酸组蛋白H3。突变胚胎的增殖细胞数量减少，DNA含量和细胞凋亡增加，以及有丝分裂纺锤体缺陷。定位克隆显示，这些表型背后的遗传缺陷是斑马鱼拓扑异构酶II α（top2a）基因突变的结果。发现Top2A是胚胎有丝分裂中脱连环化所必需的，但不是凝聚所必需的。除了发育所需外，top2a被发现是斑马鱼成年肝脏再生的单倍不足调节剂。再生分析的其他成年组织，包括鳍，没有发现杂合表型。我们的研究结果证实了脊椎动物中TOP2A的保守作用以及成人中对top2A的剂量敏感性要求。
Topoisomerases solve the topological problems encountered by DNA throughout the lifetime of a cell. Topoisomerase II alpha, which is highly conserved among eukaryotes, untangles replicated chromosomes during mitosis and is absolutely required for cell viability. A homozygous lethal mutant, can4, was identified in a screen to identify genes important for cell proliferation in zebrafish by utilizing an antibody against a mitosis-specific marker, phospho-histone H3. Mutant embryos have a decrease in the number of proliferating cells and display increases in DNA content and apoptosis, as well as mitotic spindle defects. Positional cloning revealed that the genetic defect underlying these phenotypes was the result of a mutation in the zebrafish topoisomerase II alpha (top2a) gene. top2a was found to be required for decatenation but not for condensation in embryonic mitoses. In addition to being required for development, top2a was found to be a haploinsufficient regulator of adult liver regrowth in zebrafish. Regeneration analysis of other adult tissues, including fins, revealed no heterozygous phenotype. Our results confirm a conserved role for TOP2A in vertebrates as well as a dose-sensitive requirement for top2a in adults.