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Promoter DNA Methylation of DNA Repair Genes in Cancer

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Promoter DNA Methylation of DNA Repair Genes in Cancer Promoter DNA Methylation of DNA Repair Genes in Cancer *1Shilpa V., 2Lakshmi Krishnamoorthy. 1Doctoral Scholar, Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore-560029. 2Professor and Head, Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore-560029. ABSTRACT INTRODUCTION “Epigenetics has always been all the weird and wonderful Cancer is characterized by uncontrolled cell division things that cannot be explained by genetics” a famous and malignant growth. Cancer cells have a higher quote by Denise Barlow. Coining the term epigenetics proliferation rate than their corresponding normal is credited to Conrad Waddington who describes it as tissue and they often bypass apoptosis. Furthermore, a “branch of biology which studies causal interactions they can acquire the capability to separate from their between genes and their products, which bring the original tissue and can develop metastatically in other phenotype into being”. Epigenetics adds a new stratum regions of the body. of events between genes and their expression. It proposes a control system of “switches” that turn genes on or off The expression of genetic information within an causing heritable effects in humans. Thousands of DNA individual cell dictates how that cell subsequently damaging events take place every day in our body but behaves. Events at the molecular level can influence efficient DNA repair systems prevent that. Accumulation the expression of certain genes and thereby adversely of DNA damage has been linked to cancer and genetic affect cellular functions to such a degree as to initiate deficiencies in specific DNA repair genes are associated a pathologic process. Cancer cells, for example, must with tumor prone phenotypes. Epigenetic silencing of DNA undergo a number of molecular events that allow repair genes may promote tumorigenesis. This review them to acquire several distinct pathologic behavioural summarizes current knowledge of the epigenetic inactivation properties. These properties result in deleterious of DNA repair components in cancer. clinical consequences for the host, but paradoxically empower that abnormal cell and its progeny with a survival advantage over normal cells. Much of the focus of molecular biologic research has concentrated on investigating the role of genetic Key words: Cancer, DNA Repair genes, Epigenetics, changes - that is, direct alterations of DNA base Methylation. sequence through mutation, deletion or insertion Corresponding author: Shilpa V., Department of Biochemistry, Kidwai Memorial Institute of Oncology, Dr. M. H. Marigowda Road, Bangalore-560029. Phone: 080-26094072, Fax: 080-26560723, E-mail: [email protected] 239 Shilpa V. and their effect on subsequent gene expression and EPIGENETIC featURES OF NORMAL cell behaviour. Recently, alternative mechanisms of CELL gene modulation have been observed that affect its expression and remain preserved after cell division Epigenetic mechanisms are used in many different without disrupting the actual sequence at all. ways to regulate gene expression. Epigenetic changes never involve a change in the primary DNA sequence C. H. Waddington in 1939 coined the term or a change in base pairing but are reflected primarily “Epigenetics”, which he defined as “the causal in DNA cytosine modification patterns, histone post- interactions between genes and their products, which translational modifications, or deposition of certain bring the phenotype into being”.1 Epigenetics, later histone variants along specific gene sequences. was defined as heritable changes in gene expression These epigenetic modifications of genes are generally that are not due to any alteration in the DNA reversible, but can get transmitted to the daughter sequence.2 It is increasingly apparent that, in human cells.7 cancers, heritable losses of gene function may be mediated by epigenetic as well as by genetic One common and perhaps the most permanent and abnormalities.3,4 The argument as to whether cancer is stable mechanism of epigenetic gene inactivation is an epigenetic or a genetic disease, in fact emphasizes the methylation of the 5-carbon of the DNA base that synergy between two processes drives tumor cytosine in the 5’-CpG-3’ dinucleotide sequence progression from the earliest to latest stages. Inclusion context of CpG island or promoter regions. These of epigenetic events in our concepts of how tumors methylation reactions carried out by DNA cytosine evolve heightens our need to understand the basic methyltransferases are a main component of the nature of chromatin changes that set heritable states epigenetic regulatory mechanisms in mammals.8 of gene function. From a translational standpoint, Although most CpG sites in the human genome it enriches the potential and suggests new targets are methylated, CpG dense regions known as CpG to consider for cancer prevention and therapeutic islands are typically unmethylated in normal tissue strategies. The methylation of DNA is recognized as which spans the 5’ end of the regulatory region of a key mechanism in the regulation of gene expression many genes. and evidence for its role in the development of a wide variety of cancers is rapidly accumulating.4 DNA methylation plays an essential role in normal development through its effects on gene Research into DNA methylation has been progressing imprinting, condensation of chromatin, stabilization at a furious pace, despite uncertainty about its of chromosomes, X-chromosome inactivation, tissue- origin and physiological function. Consistent with specific silencing of gene expression and transcriptional a resurgence of interest in the idea that cancer silencing of repetitive elements. 5-Methylcytosine is a disease of faulty development, there has been (m5C) was first found in DNA of higher eukaryotes a revived quest in studies to uncover epigenetic by Hotchkiss in 1948. This epigenetic regulation also processes involved in neoplastic development and coordinates gene expression during cell differentiation progression.5, 6 Epigenetic information, after all, is in mammalian embryogenesis. 9, 10 essential for development and it is clear that cancer is ultimately a disease of aberrant gene expression. The methylation of mammalian genomic DNA is catalyzed by DNA methyltransferases (DNMTs) Effective DNA repair is the backbone of cancer-free that can be divided into maintenance and de novo survival. Mutations in DNA repair genes such as DNMTs. A methyl (-CH3) group is covalently base excision repair (BER), nucleotide excision repair bonded to the 5-carbon on the cytosine base. This (NER), mismatch repair (MMR), DNA crosslink process is mediated by DNMTs. The methyl group repair, and several others is the cause of inherited is provided by S-adenosyl methionine (SAM), and cancer syndromes. As an alternative mechanism to this is converted to S-adenosyl homocysteine (SAH) genetic mutation, epigenetic gene inactivation can in the process. This is recycled back to SAM in a be brought about that either inactivates or reduces folate and cobalamin dependant pathway (Fig. 1).11 efficiency of DNA repair genes. In this review, we will discuss some examples of DNA repair mechanisms The possible existence of methylated cytosines in cancer. within DNA was known since the early part of the Austral - Asian Journal of Cancer ISSN-0972-2556, Vol. 12, No. 4, October 2013 pp 239 - 251 240 Promoter DNA Methylation of DNA Repair Genes in Cancer reversible. Such epigenetic plasticity is an excellent candidate to mediate the dynamic heterogeneity of cell populations inherent to complex tumor traits such as metastasis. In this regard, most epithelial tumors are highly invasive, and the cells relaxed can form metastatic foci, which grow within visceral organs. Two mechanisms have been proposed to account for transcriptional repression via DNA methylation. In the first mechanism, DNA methylation directly inhibits the binding of transcription factors (TFs) such as AP-2, c-Myc/ Myn, E2F and NFkB to their binding sites within promoter sequence. In this mechanism, CpG dinucleotides have Figure 1: The methylation cycle Adapted from Ref 11. Methylation of cytosine catalysed to be present within the binding site of TFs, which by DNA methyltransferase, which uses methyl group from are sensitive to methylation of CpG dinucleotides 16 SAM. (Fig. 2). The second mode of repression includes binding of proteins specific for m5CpG dinucleotides to methylated DNA. Methylated DNA recruits last century. They were initially described in the m5CpG-binding protein (MeCP) and m5CpG-binding DNA of the tubercle bacillus and subsequently were domain (MBD) proteins. MeCP1 and MeCP2 bind extracted from calf thymus, where they were known as epi-cytosine, producing a different chromotographic profile from normal cytosine.12, 13 Their purpose was not defined until relatively recently. It was speculated that they acted as a primitive host defense mechanism to silence DNA from viral organisms and provided an explanation for the latency of certain viral infections and how such agents can escape detection.14, 15 EPIGENETIC CHANGES IN caNCER Promoter hypermethylation for down regulating genes has been known to play a critical role in tumorigenesis. Genes that are unmethylated in normal tissues at all ages are also found to be hypermehtylated quite early in tumorigenesis. These early losses of cell cycle control, altered regulation Figure 2: Repression of transcription via
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