Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases
Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases
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DOI：
10.3390/genes10050369
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发表时间：
2019-05
期刊：
影响因子：
3.5
通讯作者：
Allison B. Norvil;Debapriya Saha;Mohd Saleem Dar;H. Gowher
中科院分区：
文献类型：
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作者：
Allison B. Norvil;Debapriya Saha;Mohd Saleem Dar;H. Gowher
尽管大量证据支持异常 DNA 甲基化在多种人类疾病病因学中的作用，但调节哺乳动物 DNA 甲基转移酶 (DNMT) 活性的基本机制尚未完全了解。全基因组关联研究的最新进展有助于识别各种疾病中 DNMT 的突变和遗传改变，这些突变和改变有可能影响这些酶的生物学功能和活性。其中一些突变是种系传播的，并与许多遗传性疾病相关，这些遗传性疾病可能是由基因组调控区室中异常的 DNA 甲基化模式引起的。这些遗传性疾病通常会导致神经功能障碍、生长缺陷和遗传性癌症。 DNMT 变体的生化和生物学表征可以揭示这些酶的分子机制并深入了解它们的特定功能。在这篇综述中，我们介绍了 DNA 甲基化和 DNMT 的作用和调控。我们讨论了与罕见疾病相关的 DNMT 突变、这些突变对酶活性的特征性影响，并根据这些蛋白质的已知晶体结构提供了对其潜在影响的见解。
Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have helped identify mutations and genetic alterations of DNMTs in various diseases that have a potential to affect the biological function and activity of these enzymes. Several of these mutations are germline-transmitted and associated with a number of hereditary disorders, which are potentially caused by aberrant DNA methylation patterns in the regulatory compartments of the genome. These hereditary disorders usually cause neurological dysfunction, growth defects, and inherited cancers. Biochemical and biological characterization of DNMT variants can reveal the molecular mechanism of these enzymes and give insights on their specific functions. In this review, we introduce roles and regulation of DNA methylation and DNMTs. We discuss DNMT mutations that are associated with rare diseases, the characterized effects of these mutations on enzyme activity and provide insights on their potential effects based on the known crystal structure of these proteins.