Department of Biochemistry and Molecular Biology, Georgia Health Sciences University Cancer Center, CN-2151, 1410 Laney Walker Blvd, Augusta, GA 30912, USA.
Adv Exp Med Biol. 2013;754:3-29. doi: 10.1007/978-1-4419-9967-2_1.
The maintenance DNA methyltransferase (DNMT) 1 and the de novo methyltransferases DNMT3A and DNMT3B are all essential for mammalian development. DNA methylation, catalyzed by the DNMTs, plays an important role in maintaining genome stability. Aberrant expression of DNMTs and disruption of DNA methylation patterns are closely associated with many forms of cancer, although the exact mechanisms underlying this link remain elusive. DNA damage repair systems have evolved to act as a genome-wide surveillance mechanism to maintain chromosome integrity by recognizing and repairing both exogenous and endogenous DNA insults. Impairment of these systems gives rise to mutations and directly contributes to tumorigenesis. Evidence is mounting for a direct link between DNMTs, DNA methylation, and DNA damage repair systems, which provide new insight into the development of cancer. Like tumor suppressor genes, an array of DNA repair genes frequently sustain promoter hypermethylation in a variety of tumors. In addition, DNMT1, but not the DNMT3s, appear to function coordinately with DNA damage repair pathways to protect cells from sustaining mutagenic events, which is very likely through a DNA methylation-independent mechanism. This chapter is focused on reviewing the links between DNA methylation and the DNA damage response.
维持性 DNA 甲基转移酶 (DNMT) 1 和从头甲基转移酶 DNMT3A 和 DNMT3B 对于哺乳动物的发育都是必不可少的。由 DNMT 催化的 DNA 甲基化在维持基因组稳定性方面起着重要作用。DNMTs 的异常表达和 DNA 甲基化模式的破坏与许多形式的癌症密切相关,尽管这种联系的确切机制仍不清楚。DNA 损伤修复系统已经进化为一种全基因组监测机制,通过识别和修复外源和内源性 DNA 损伤来维持染色体的完整性。这些系统的损伤会导致突变,并直接促进肿瘤发生。越来越多的证据表明,DNMTs、DNA 甲基化和 DNA 损伤修复系统之间存在直接联系,为癌症的发展提供了新的见解。与肿瘤抑制基因一样,一系列 DNA 修复基因在多种肿瘤中经常受到启动子过度甲基化的影响。此外,DNMT1 而不是 DNMT3s 似乎与 DNA 损伤修复途径协同作用,以保护细胞免受致突变事件的影响,这很可能是通过一种非 DNA 甲基化依赖的机制。本章重点讨论 DNA 甲基化与 DNA 损伤反应之间的联系。