TDG介导的去甲基化在细胞发育分化及肿瘤发生中的研究进展

Research progress of TDG-mediated demethylation in cell development, cell differentiation and tumorigenesis

关键词:  胸腺嘧啶DNA糖苷酶  DNA去甲基化  胚胎发育  细胞分化  衰老  癌症

Key words:  thymine DNA glycosylase  DNA demethylation  embryo development  cell differen-tiation  aging  cancer

摘要:

DNA甲基化是一种重要的表观遗传修饰，可对生命发生发展阶段中的基因表达进行调控。近来研究发现，胸腺嘧啶DNA糖苷酶（thymine DNA glycosylase, TDG）是能特异修复G: T错配的酶，在DNA去甲基化过程中起到重要作用。TDG与TET、AID、Gadd45a等蛋白协同，通过碱基切除修复（base excision repair, BER）作用参与DNA去甲基化过程。此外，TDG介导的BER作用能去除甲基化中间产物的5-羟甲基胞嘧啶（5-hydroxymethylcytosine, 5hmC）及其衍生物的积累、消除5-甲基胞嘧啶（5-methylcyosine, 5mC）自发脱氨基导致的突变，保持基因组的遗传稳定性。TDG的表达下降或酶的失活会引起基因组稳定性降低，增加肿瘤发生的风险。TDG介导的DNA去甲基化修饰调节影响胚胎发育、细胞分化与衰老的过程，其对癌症的发生也有着不可忽视的作用。

Abstract:

DNA methylation is an important epigenetic modification that regulates gene expression during the development of life. Thymidine DNA glycosylase (TDG) is an enzyme for specifically repairing G: T mismatch found in recent years, which plays an important role in DNA demethylation. Cooperated with proteins such as TET, AID and Gadd45a, TDG participates in DNA demethylation by base excision repair (BER). In addition, TDG-mediated BER can remove the accumulation of methylated intermediates 5-hydroxymethylcytosine (5hmC) and its derivatives, and eliminate mutations caused by spontaneous deamination of 5-methylcytosine (5mC), thereby maintaining the genetic stability of the genome. Deregulation of TDG will cause genomic instability, leading to tumorigenesis. This TDG-mediated regulation of DNA methylation profoundly affects the process of embryonic development, cell differentiation and aging, and it also plays an important role in the occurrence of cancer.