Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease
Erasure of Tet-Oxidized 5-Methylcytosine by a SRAP Nuclease
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DOI：
10.1016/j.celrep.2017.09.055
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发表时间：
2017-10-10
期刊：
影响因子：
8.8
通讯作者：
Feldman, Douglas E.
中科院分区：
文献类型：
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作者：
Kweon, Soo-Mi;Zhu, Bing;Feldman, Douglas E.
泰特双加氧酶对DNA中5-甲基胞嘧啶（5 mC）的酶促氧化可重新编程胚胎发生和出生后发育中的基因组功能。5 mC的Tet-oxidized衍生物，如5-羟甲基胞嘧啶（5 hmC），在DNA去甲基化中作为短暂的中间体或作为持久的标记持续存在，但这些替代命运如何在单个CpG上指定尚不清楚。在这里，我们报告SOS反应相关肽酶（SRAP）结构域蛋白SRAP 1，与细菌中的DNA损伤反应操纵子相关的古老蛋白质超家族的哺乳动物直系同源物，与DNA中的Tet-oxidized形式的5 mC结合，并催化这些碱基通过自肽酶偶联核酸酶转化为未修饰的胞嘧啶。小鼠Srap 1的双等位基因失活导致与异位5 hmC广泛积累相关的胚胎亚致死性。这些研究结果建立了一类DNA碱基修饰选择性核酸酶的功能，并将SRAP 1定位为哺乳动物胚胎发育过程中5 mC去甲基化轨迹的决定因素。
Enzymatic oxidation of 5-methylcytosine (5mC) in DNA by the Tet dioxygenases reprograms genome function in embryogenesis and postnatal development. Tet-oxidized derivatives of 5mC such as 5-hydroxymethylcytosine (5hmC) act as transient intermediates in DNA demethylation or persist as durable marks, yet how these alternative fates are specified at individual CpGs is not understood. Here, we report that the SOS response-associated peptidase (SRAP) domain protein Srap1, the mammalian ortholog of an ancient protein superfamily associated with DNA damage response operons in bacteria, binds to Tet-oxidized forms of 5mC in DNA and catalyzes turnover of these bases to unmodified cytosine by an autopeptidase-coupled nuclease. Biallelic inactivation of murine Srap1 causes embryonic sublethality associated with widespread accumulation of ectopic 5hmC. These findings establish a function for a class of DNA base modification-selective nucleases and position Srap1 as a determinant of 5mC demethylation trajectories during mammalian embryonic development.