Valinluck Victoria, Liu Pingfang, Kang Joseph I, Burdzy Artur, Sowers Lawrence C
Department of Biochemistry and Microbiology, School of Medicine, Loma Linda University Loma Linda, CA 92350, USA.
Nucleic Acids Res. 2005 May 25;33(9):3057-64. doi: 10.1093/nar/gki612. Print 2005.
Perturbations in cytosine methylation signals are observed in the majority of human tumors; however, it is as yet unknown how methylation patterns become altered. Epigenetic changes can result in the activation of transforming genes as well as in the silencing of tumor suppressor genes. We report that methyl-CpG-binding proteins (MBPs), specific for methyl-CpG dinucleotides, bind with high affinity to halogenated pyrimidine lesions, previously shown to result from peroxidase-mediated inflammatory processes. Emerging data suggest that the initial binding of MBPs to methyl-CpG sequences may be a seeding event that recruits chromatin-modifying enzymes and DNA methyltransferase, initiating a cascade of events that result in gene silencing. MBD4, a protein with both methyl-binding and glycosylase activity demonstrated repair activity against a series of 5-substituted pyrimidines, with the greatest efficiency against 5-chlorouracil, but undetectable activity against 5-chlorocytosine. The data presented here suggest that halogenated pyrimidine damage products can potentially accumulate and mimic endogenous methylation signals.
在大多数人类肿瘤中都观察到胞嘧啶甲基化信号的扰动；然而，甲基化模式如何改变至今仍不清楚。表观遗传变化可导致转化基因的激活以及肿瘤抑制基因的沉默。我们报告，对甲基-CpG二核苷酸具有特异性的甲基-CpG结合蛋白（MBP）与卤代嘧啶损伤具有高亲和力，此前已证明卤代嘧啶损伤是由过氧化物酶介导的炎症过程引起的。新出现的数据表明，MBP与甲基-CpG序列的初始结合可能是一个引发事件，可招募染色质修饰酶和DNA甲基转移酶，引发一系列导致基因沉默的事件。MBD4是一种具有甲基结合和糖基化酶活性的蛋白质，对一系列5-取代嘧啶表现出修复活性，对5-氯尿嘧啶的修复效率最高，但对5-氯胞嘧啶没有可检测到的活性。此处呈现的数据表明，卤代嘧啶损伤产物可能会潜在地积累并模拟内源性甲基化信号。
