DNA主动去甲基化相关通路的研究进展

doi:10.3969/j.issn.1673-8640.2013.03.021

摘要/Abstract

摘要： 对于DNA去甲基化的研究以往都是以DNA甲基转移酶（DNA methyltransferase，DNMT）为靶向分子，通过抑制DNMT来恢复抑癌基因的功能，从而达到治疗肿瘤的目的。去甲基化药物就是通过抑制DNMT的活性使复制后的DNA不能再次甲基化，从而导致所有等位基因表现为去甲基化，使抑癌基因得以恢复表达，抑制肿瘤的生长。虽然去甲基化药物的出现将肿瘤的治疗带到了一个新的高度，但是仍有很多问题亟待解决，比如DNA去甲基化的确切机制及其靶向特异性。目前研究发现DNA去甲基化主要有两种方式：一种是在原生殖细胞和早期胚胎中都可以发生的主动DNA去甲基化^[1]，这一过程不依赖于DNA复制，受酶的催化，使5-甲基胞嘧啶(5-methylcytosine，5mC)转化为未甲基化的胞嘧啶；另一种是通过与复制相关的过程发生的被动DNA去甲基化^[2]，即在DNA复制时，DNA甲基化模式的维持受到干扰，没有保留原有甲基化模式，随着复制的进行，甲基化的CpG岛被“稀释”，导致DNA去甲基化。尽管在很多细胞进程中都存在DNA主动去甲基化，但是关于主动去甲基化的潜在机制仍存在很多争论^[3]。目前研究发现DNA主动去甲基化可能涉及到的通路有6个，即5mC脱氨基化与BER偶联通路、碱基切除修复（base excision repair，BER）通路、5mC甲基团脱氢通路、核苷切除修复（nucleoside resection repair，NER）通路、水解反应直接去除甲基团、5mC氧化去甲基化^[3-5]。与这些通路相关的酶和因子有：胞嘧啶脱氨酶：AID，APOBEC1^[6-7]；TET蛋白：TET1，TET2等^[8-9]；延伸复合物蛋白：ELP1，ELP2等^[10]；碱基切除修复蛋白：RNF4，TDG等 ^{[11-13]；核苷酸切除酶：GADD45a，GADD45b^[14-15]；DNA甲基转移酶：DNMT3a，DNMT3b；DNA糖基化酶：EME，DML2等^[16-17]。但其中哪个或哪些具有真正的DNA去甲基化活性尚待验证。本文综述最新文献资料，介绍其中主要通路及其相关的酶和因子。}

金巧智1 综述，蔡志毅2 审校. DNA主动去甲基化相关通路的研究进展[J]. 检验医学, 2013, 28(3): 243-247.

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