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[复制性和复制后DNA甲基化作为细胞中突变产生机制的研究]

[The mechanism of replicative and post-replicative DNA methylation as a generator of mutations in a cell].

作者信息

Mazin A L

出版信息

Mol Biol (Mosk). 1993 Sep-Oct;27(5):965-79.

PMID:8246940
Abstract

The functional role of enzymatic DNA methylation in eukaryotes is still obscure even 45 years after its discovery. In the present paper the analysis of various aspects of DNA methylation has been made from the point of view of a common functional model considering the system as a generator of 5mC-->T mutations in the cell. The mechanism and consequences of the reactions have been described in detail, from the 5mC residue deamination during replicative DNA methylation and repair of G.T-mispairs to production of hemimethylated sites in DNA and their postreplicative methylation. It was shown that the loss of the most part of the 5mC residues from DNA during the lifespan proceeds with aging both of organism's tissues and of cell cultures. Evidence was obtained that this is the result of gradual accumulation of 5mC-->T + C transitions in the genome during each cell division. Such substitutions take place 10 times more often in methylated sites *CG than in any other sites of DNA. They disproportionally contribute to general mutagenesis and may be a cause of many hereditary human diseases. The conclusion has been made that DNA methylation can be considered as a genetically programmed mechanism for accumulating mutations with aging.

摘要

酶促DNA甲基化在真核生物中的功能作用,即使在其发现45年后仍不清楚。在本文中,从一个通用功能模型的角度对DNA甲基化的各个方面进行了分析,该模型将该系统视为细胞中5mC→T突变的产生者。详细描述了这些反应的机制和后果,从复制性DNA甲基化过程中5mC残基的脱氨基以及G.T错配的修复,到DNA中半甲基化位点的产生及其复制后甲基化。结果表明,在生物体组织和细胞培养物衰老的整个生命周期中,DNA中大部分5mC残基会随着衰老而丢失。有证据表明,这是基因组在每次细胞分裂过程中5mC→T + C转换逐渐积累的结果。这种替换在甲基化位点*CG中发生的频率比在DNA的任何其他位点高10倍。它们对一般诱变有不成比例的贡献,可能是许多人类遗传性疾病的原因。得出的结论是,DNA甲基化可被视为一种随着衰老积累突变的基因编程机制。

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