Smith S S
Department of Cell and Tumor Biology, City of Hope National Medical Center, Duarte, CA 91010-3000, USA.
Int J Mol Med. 1998 Jan;1(1):147-56.
As a consequence of their mechanism of action, DNA (cytosine-5) methyltransferases from both prokaryotes and eukaryotes necessarily recognize mispaired bases in unusual DNA structures as catalytic transition-state analogs. A review of the available data suggests that the enzymes are designed to stall at these sites because they are unable to release substrates or products that are fixed in a conformation resembling the transition state. The enzymes can operate by a two-step process in which they first methylate extrahelical cytosines satisfying their recognition requirements and subsequently stall at the site of methylation. On RNA and DNA RNA hybrids they may operate by a similar one-step process in which they stall at transition-state analogs without methylating cytosine moieties. These natural capacities suggest that the enzymes may physically participate in stable nucleoprotein assemblies formed as components of normal chromatin structure or as intermediates in the repair of unusual structures. The methyltransferases, themselves, may physically participate in chromosome remodelling as part of a mechanism of inactivation or imprinting by stabilizing RNA DNA hybrids or RNA RNA secondary structure involving cis-acting untranslated RNAs like the product of the Xist gene. Methyl-transferase may physically participate in the repair of certain unusual structures by serving as a nucleation point. The affinity for secondary structure in nucleic acids may account for the spreading of DNA methylation patterns. Titration of host methyltransferase by RNA DNA hybrids and RNA secondary structure formed during retroviral replication in certain tumorigenic retroviruses, like MMTV, may account for global hypomethylation observed in retrovirally transformed cells. In a similar fashion, titration of methyltransferase by secondary structures associated with chromosome instability may account for global hypomethylation observed in association with local hypermethylation in tumorigenesis.
由于其作用机制，原核生物和真核生物的DNA（胞嘧啶-5）甲基转移酶必然会将异常DNA结构中的错配碱基识别为催化过渡态类似物。对现有数据的综述表明，这些酶被设计为在这些位点停滞，因为它们无法释放固定在类似过渡态构象中的底物或产物。这些酶可以通过两步过程发挥作用，其中它们首先甲基化满足其识别要求的螺旋外胞嘧啶，随后在甲基化位点停滞。在RNA和DNA-RNA杂交体上，它们可能通过类似的一步过程发挥作用，即在过渡态类似物处停滞而不甲基化胞嘧啶部分。这些天然能力表明，这些酶可能实际参与作为正常染色质结构组成部分或作为异常结构修复中间体形成的稳定核蛋白组装。甲基转移酶本身可能作为失活或印记机制的一部分实际参与染色体重塑，通过稳定RNA-DNA杂交体或涉及顺式作用非翻译RNA（如Xist基因产物）的RNA-RNA二级结构。甲基转移酶可能作为成核点实际参与某些异常结构的修复。对核酸二级结构的亲和力可能解释了DNA甲基化模式的扩散。在某些致瘤逆转录病毒（如MMTV）的逆转录病毒复制过程中形成的RNA-DNA杂交体和RNA二级结构对宿主甲基转移酶的滴定，可能解释了在逆转录病毒转化细胞中观察到的整体低甲基化。以类似的方式，与染色体不稳定性相关的二级结构对甲基转移酶的滴定，可能解释了在肿瘤发生中与局部高甲基化相关的整体低甲基化。
