Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration.
Tet3 Reads 5-Carboxylcytosine through Its CXXC Domain and Is a Potential Guardian against Neurodegeneration.
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DOI：
10.1016/j.celrep.2015.12.044
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发表时间：
2016-01-26
期刊：
影响因子：
8.8
通讯作者：
Pfeifer GP
中科院分区：
文献类型：
--
作者：
Jin SG;Zhang ZM;Dunwell TL;Harter MR;Wu X;Johnson J;Li Z;Liu J;Szabó PE;Lu Q;Xu GL;Song J;Pfeifer GP
我们报道了哺乳动物5-甲基胞嘧啶(5mC)氧化酶Tet3以三种主要亚型存在，并鉴定了含有N-末端CXXC结构域的全长亚型(Tet3FL)。这个CXXC结构域与未甲基化的CPGS结合，但出人意料的是，它与5-羧基胞嘧啶(5caC)的亲和力最高。我们测定了CXXC结构域-5caC-DNA复合体的晶体结构，揭示了该结构域作为CcaCG序列阅读器的结合特异性的结构基础。Tet3FL在神经细胞中的定位表明，Tet3FL精确定位于参与溶酶体功能、mRNA加工和碱基切除修复途径关键基因的转录起始点(TSS)。因此，Tet3FL可能通过碱基切除修复来调节5caC的去除。在大脑有丝分裂后神经元中，Tet3FL主动清除编码溶酶体蛋白基因的TSS中积累的5mC可能对预防神经退行性疾病具有重要意义。
We report that the mammalian 5-methylcytosine (5mC) oxidase Tet3 exists as three major isoforms and characterized the full-length isoform containing an N-terminal CXXC domain (Tet3FL). This CXXC domain binds to unmethylated CpGs but unexpectedly its highest affinity is towards 5-carboxylcytosine (5caC). We determined the crystal structure of the CXXC domain - 5caC-DNA complex revealing the structural basis of the binding specificity of this domain as a reader of CcaCG sequences. Mapping of Tet3FL in neuronal cells shows that Tet3FL is localized precisely at the transcription start sites (TSS) of genes involved in lysosome function, mRNA processing and key genes of the base excision repair pathway. Thus, Tet3FL may function as a regulator of 5caC removal by base excision repair. Active removal of accumulating 5mC from the TSS of genes coding for lysosomal proteins by Tet3FL in postmitotic neurons of the brain may be important for preventing neurodegenerative diseases.