Misregulation of the expression and activity of DNA methyltransferases in cancer.
Misregulation of the expression and activity of DNA methyltransferases in cancer.
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DOI：
10.1093/narcan/zcab045
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发表时间：
2021-12
期刊：
影响因子：
5.1
通讯作者：
Gowher H
中科院分区：
文献类型：
--
作者：
Mensah IK;Norvil AB;AlAbdi L;McGovern S;Petell CJ;He M;Gowher H
在哺乳动物中，DNA 甲基转移酶 DNMT1 和 DNMT3（A、B 和 L）在分裂和非分裂细胞中沉积并维持 DNA 甲基化。尽管这些酶具有不显着的 DNA 序列特异性 (CpG)，但它们的区域特异性受到与各种蛋白质因子、染色质修饰剂和组蛋白翻译后修饰的相互作用的调节。 DNMT 表达或相互作用伙伴的变化会影响 DNA 甲基化模式。因此，获得的基因表达可能会增加细胞的增殖潜力，通常伴随着癌症中发现的细胞特性的丧失。因此，异常的 DNA 甲基化，包括各个基因组区域的高甲基化和低甲基化，是大多数癌症的标志。此外，影响催化活性的 DNMT 体细胞突变也在急性髓系白血病癌细胞中被定位。尽管对某些癌症非常有效，但临床批准的 DNMT 抑制剂缺乏特异性，这可能会导致广泛的有害影响。阐明 DNMT 的独特分子机制将有助于发现替代的癌症治疗靶点。本综述的重点是：(i) DNMT 的结构和特征，(ii) 癌症中 DNMT 突变和异常表达的发生率，(iii) 介导其异常表达的因素，以及 (iv) 异常 DNMT 复合物在癌症中的影响。癌症中 DNMT 活性的调节。
In mammals, DNA methyltransferases DNMT1 and DNMT3’s (A, B and L) deposit and maintain DNA methylation in dividing and nondividing cells. Although these enzymes have an unremarkable DNA sequence specificity (CpG), their regional specificity is regulated by interactions with various protein factors, chromatin modifiers, and post-translational modifications of histones. Changes in the DNMT expression or interacting partners affect DNA methylation patterns. Consequently, the acquired gene expression may increase the proliferative potential of cells, often concomitant with loss of cell identity as found in cancer. Aberrant DNA methylation, including hypermethylation and hypomethylation at various genomic regions, therefore, is a hallmark of most cancers. Additionally, somatic mutations in DNMTs that affect catalytic activity were mapped in Acute Myeloid Leukemia cancer cells. Despite being very effective in some cancers, the clinically approved DNMT inhibitors lack specificity, which could result in a wide range of deleterious effects. Elucidating distinct molecular mechanisms of DNMTs will facilitate the discovery of alternative cancer therapeutic targets. This review is focused on: (i) the structure and characteristics of DNMTs, (ii) the prevalence of mutations and abnormal expression of DNMTs in cancer, (iii) factors that mediate their abnormal expression and (iv) the effect of anomalous DNMT-complexes in cancer. Modulation of DNMT activity in cancer.