1] Genome Damage and Stability Centre, School of Biological Sciences, University of Sussex, Sussex, UK. [2].
1] Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. [2] Department of Cognitive Neurosciences, Donders Institute for Brain Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands. [3].
Nat Genet. 2014 May;46(5):516-21. doi: 10.1038/ng.2929. Epub 2014 Mar 23.
Topoisomerase II (TOP2) removes torsional stress from DNA and facilitates gene transcription by introducing transient DNA double-strand breaks (DSBs). Such DSBs are normally rejoined by TOP2 but on occasion can become abortive and remain unsealed. Here we identify homozygous mutations in the TDP2 gene encoding tyrosyl DNA phosphodiesterase-2, an enzyme that repairs 'abortive' TOP2-induced DSBs, in individuals with intellectual disability, seizures and ataxia. We show that cells from affected individuals are hypersensitive to TOP2-induced DSBs and that loss of TDP2 inhibits TOP2-dependent gene transcription in cultured human cells and in mouse post-mitotic neurons following abortive TOP2 activity. Notably, TDP2 is also required for normal levels of many gene transcripts in developing mouse brain, including numerous gene transcripts associated with neurological function and/or disease, and for normal interneuron density in mouse cerebellum. Collectively, these data implicate chromosome breakage by TOP2 as an endogenous threat to gene transcription and to normal neuronal development and maintenance.
拓扑异构酶 II（TOP2）消除 DNA 的扭转力，并通过引入瞬时 DNA 双链断裂（DSB）来促进基因转录。这种 DSB 通常由 TOP2 重新连接，但有时会变得无效并保持未封闭。在这里，我们在编码酪氨酸 DNA 磷酸二酯酶-2 的 TDP2 基因中鉴定出纯合突变，该酶可修复“无效”的 TOP2 诱导的 DSB，该突变存在于智力障碍、癫痫和共济失调的个体中。我们表明，受影响个体的细胞对 TOP2 诱导的 DSB 高度敏感，并且 TDP2 的缺失抑制了培养的人类细胞和经过无效 TOP2 活性后处于有丝分裂后阶段的小鼠神经元中的 TOP2 依赖性基因转录。值得注意的是，TDP2 对于发育中的小鼠大脑中许多基因转录本的正常水平也是必需的，包括与神经功能和/或疾病相关的许多基因转录本，以及对于小鼠小脑内正常中间神经元密度也是必需的。总之，这些数据表明 TOP2 的染色体断裂是对基因转录以及正常神经元发育和维持的内源性威胁。
