DNA methyltransferase expression differs with proliferation in childhood acute lymphoblastic leukemia

Abstract

DNA methylation is involved in genomic imprinting, tissue and stage specific gene regulation, X chromosome inactivation and especially necessary in normal mammalian development [1]. Methylation of DNA at cytosine base occurs at most CpG islands in the mammalian genome, with exception of CpG islands of gene promoters which are usually unmethylated. Methylation of promoter CpG islands inhibits the activity of the gene by inhibiting the association of some DNA-binding factors with methylated DNA sequences or by silencing transcription via methyl-CpG binding proteins with co-repressors and chromatin modifiers [2]. Cancer is known as a genetic disease, in which epigenetic alterations play important roles. Cancer cells show global genomic hypomethylation, but the CpG islands of the promoters, especially the promoters of the tumour suppressor genes are hypermethylated [3]. Aberrant methylation of CpG islands is a major epigenetic mechanism of gene expression in human cancers. Global hypomethylation is important in tumour formation by different ways which include chromosomal and genomic instability, increased mutation rate and recombination frequency [4]. Hypermethylation of tumour suppressor genes causes gene inactivation, furthermore aberrant DNA methylation facilitates gene mutation, because deamination of 5-methylcytosine leads to the formation of thymine which is not repaired by uracil glycosylases, instead of the formation of uracil by cytosine deamination [5]. Acute lymphoblastic leukemia (ALL), is the most frequent cancer of childhood (25%). The blockage of lymhpoid cell development at any stage, leads to ALL. Chromosomal aberrations as well as epigenetic changes are important in it’s development. E-cadherin, DAP-kinase, p73 and p15 gene promoters are some of the gene promoters that are known to be hypermethylated in childhood ALL [6–8]. DNA methyltransferases (DNMT’s) are the enzymes that methylate DNA. In mammalians, there are five different DNMT’s: DNMT1, DNMT2, DNMT3A, DNMT3B and DNMT3L. All of the DNMT’s, except DNMT3L, are catalitically active. All have a catalytic carboxy terminal and a regulator amino terminal, except DNMT2. The activity of DNMTs are greatly regulated by their amino terminal domain which interacts with other molecules. DNMT2, contains only the catalytic domain and participates scarcely to the formation of DNA methylation pattern although it covalently binds to DNA [9–11]. DNMT1 targets the replication fork, methylates preferentially hemimethylated DNA, and is responsible for the Isik Bokesoy—Retired Professor.