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Review Article DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations

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Review Article DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Crossref Hindawi Oxidative Medicine and Cellular Longevity Volume 2017, Article ID 3179421, 16 pages https://doi.org/10.1155/2017/3179421 Review Article DNA Oncogenic Virus-Induced Oxidative Stress, Genomic Damage, and Aberrant Epigenetic Alterations 1 1 2 Mankgopo Magdeline Kgatle, Catherine Wendy Spearman, Asgar Ali Kalla, and 1 Henry Norman Hairwadzi 1Division of Hepatology, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa 2Division of Rheumatology, Department of Medicine, Faculty of Health Sciences, Groote Schuur Hospital, Cape Town, South Africa Correspondence should be addressed to Mankgopo Magdeline Kgatle; [email protected] Received 27 January 2017; Revised 1 May 2017; Accepted 23 May 2017; Published 27 June 2017 Academic Editor: Peeter Karihtala Copyright © 2017 Mankgopo Magdeline Kgatle et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Approximately 20% of human cancers is attributable to DNA oncogenic viruses such as human papillomavirus (HPV), hepatitis B virus (HBV), and Epstein-Barr virus (EBV). Unrepaired DNA damage is the most common and overlapping feature of these DNA oncogenic viruses and a source of genomic instability and tumour development. Sustained DNA damage results from unceasing production of reactive oxygen species and activation of inflammasome cascades that trigger genomic changes and increased propensity of epigenetic alterations. Accumulation of epigenetic alterations may interfere with genome-wide cellular signalling machineries and promote malignant transformation leading to cancer development. Untangling and understanding the underlying mechanisms that promote these detrimental effects remain the major objectives for ongoing research and hope for effective virus-induced cancer therapy. Here, we review current literature with an emphasis on how DNA damage influences HPV, HVB, and EBV replication and epigenetic alterations that are associated with carcinogenesis. 1. Introduction described. Oncogenic viruses like HBV typically activate oxi- dative stress-mediated signalling mechanisms that influence Carcinogenesis is a multistep process characterised by abnor- an inflammatory cell migration leading to mutations and tis- mal growth and proliferation of cells that result from repeated sue damage [5, 6]. Some oncoviruses harbour tumorigenic or cycles of aberrant genetic and epigenetic modifications, which oncogenic materials that enable them to escape the host alter asubstantial amount of human genes especially immuno- immune defence mechanisms and establish persistent infec- regulatory, tumour suppressors, and oncogenes. It proceeds tion. This ultimately predisposes to carcinogenesis by hijack- when the body’s normal control machineries such as cell cycle ing the host’s checkpoint-controlling cell machineries [7, 8]. arrest and programmed cell death are disrupted, leading to Host genomic instability and disrupted cellular machinery malignant transformation and subsequently tumour forma- effects from genome-wide mutations and epigenetic alter- tion [1, 2]. Although all human cancers are noncommunicable ations clearly seem accountable for the pernicious facet of diseases, approximately 20% of their global burden is attribut- oncovirus-induced carcinogenesis [9]. able to DNA oncoviruses [2, 3]. Three well-studied DNA oncogenic viruses include human papillomavirus (HPV), hep- atitis B virus (HBV), and Epstein-Barr virus (EBV). EBV, 2. Oncogenic Virus-Induced Reactive Oxygen HBV, and HPV infections are associated with gastric, hepato- Species and DNA Damage cellular carcinomas, and cervical cancers, respectively [4]. Several mechanisms that underlie the ability of oncogenic Chronic inflammatory responses triggered by persistent viral viruses to transform normal cells to cancer cells have been infection usually lead to unceasing production of reactive 2 Oxidative Medicine and Cellular Longevity oxygen species (ROS). ROS are highly reactive oxygen- functions by abnormally switching “on” and “off” different containing radicals expressed mainly by neutrophils and genes. DNA methylation, histone modification, and noncod- phagocytes as part of host defence mechanisms against path- ing mRNAs are special chemical marks of epigenetics that ogens [10]. ROS cooperates with reactive nitrogen species cooperate in determining whether a gene is accessible for read- (RNS), and collectively, they form RONS [11]. RONS gener- ing, and they contribute to cancer initiation, progression, ates DNA damage and activation of DNA damage response metastases, and chemoresistance. Epigenetic errors are driven (DDR) proteins that promote tissue injury at the site of by a spectrum of enzymes including DNA methyltransferases inflammation. Under sustained viral-induced environmental (DNMT1, DNMT3A, and DNMT3B), histone acetyltransfer- stress, activated phagocytic cells may result in overexpression ases (HATs), and histone deacetylases (HDACs). DNMTs are of RONS that alter the microenvironment and cause defec- epigenetic writers that attach methyl groups to the nucleotide tive DNA repair and damage [12]. These effects are critically sequence whereas HDACs erase the acetyl groups from important and may lead to chromosomal alterations that histones. Dimethylation of histone 3 lysine 9 (H3K9me2) promote genome instability, mutations, and epigenetic adap- and trimethylation of H3K9 (H3K9me3), H3K27me3, and tations in cellular machinery systems that normally suppress H4K20me3 typically mark transcriptionally silent chromatin. tumorigenesis [3]. DNA viruses may encode oncogenic genes These epigenetic mediators are important in normal develop- that are also capable of hijacking host cellular mechanisms to ment and cell differentiation. H3K27me3 and H4K20me3 are regulate cell survival and propagation. When these oncogenic activated by enhancer of zeste homologue 2 (EZH2) and form genes overcome the ability of host cell machinery to control part of polycomb repressive complex 2 (PRC2). PRC2 is one of homeostasis, they trigger the tumour microenvironment the polycomb-group (PcG) proteins that regulate gene associated with an elevated level of mutations that cause transcription by inducing epigenetics through EZH2, and it malignant transformation and ultimately cancer [8]. is associated with transcriptional repression of H3K27me2 ROS regulates inflammasomes in response to oncogenic and H3K27me3. viral infections [10, 13, 14]. Inflammasomes are important Intimate link between genome oxidative damage and component of the innate immune system that are recruited epigenetics have been fairly described, and it suggests that to a damaged site to facilitate tissue repair. They activate a oxidative DNA damage is a contributing factor in the induc- key inflammatory mediator known as caspase-1 and promote tion of epigenetic alterations [22]. O’Hagan et al. [22] have inflammation in response to invading pathogens. Amongst shown that epigenetic drivers such as DNMT1, DNMT3b, several inflammasomes are interferon gamma-inducible pro- EZH2, and SIRT1 are recruited at the site of DNA damage to tein 16 (IFI16), absent in melanoma 2 (AIM2), apoptosis- establish and maintain silence in gene transcription. 5- associated speck-like protein containing a CARD (ACS), hydroxymethylcytosine (5hmC), an oxidised product from NLR-family apoptosis inhibitory protein (NAIP), NOD-like 5-methylcytosine, was also shown to localise to the sites of receptor-family CARD domain containing protein 4 endogenous DNA damage and promote repair, indicating its (NLRC4), NLR family pyrin domain containing 1 (NLRP1), role in genomic integrity [23]. Zhang et al. [24] have recently and NLRP3 [15, 16]. Caspase-1 cooperates with ACS to demonstrated that knockdown of ten-eleven translocation induce inflammasomes by secreting proinflammatory cyto- (TET) 2 protein reverses aberrant oxidative stress-induced kines pro-interleukin- (pro-IL-) 1β and pro-IL-18 into their upregulation of DNMT1 and 5-hydroxymethylcytosine active form IL-1β and IL-18 [15]. This influences cell survival (5hmC) in cancer, suggesting a protective role of TET2 against by inducing pyroptosis through inactivation of IL-33, a tran- DNA damage. Chromodomain helicase DNA binding protein scriptional regulator of NF-κB p65 subunit. AIM2 initiates 4 (CHD4) is a nucleosome remodelling and deacetylation caspase-1 activation and inflammasomes by binding to for- (NuRD) enzyme. It is usually recruited to the DNA damaged eign cytoplasmic dsDNA and its adaptor ACS. Upregulated sites to promote genome stability of DSBs and cell survival AIM2 significantly correlates with increased inflammation via interaction with rapid poly(ADP-ribosyl)ated proteins in chronic HBV infection, and this was found to induce renal and ubiquitin ligase RING finger protein 8 [25–27]. CHd4 damage in the presence of glomerulonephritis [17–19]. was also shown to regulate G1/S transition by regulating dea- 7,8-Dihydro-8-oxoguanine (8-oxoG) is a major form of cetylation of p53 tumour suppressor gene that plays a central oxidative DNA damage generated from ROS. Accumulation role in the DNA damage response. Induction of DSBs was of 8-oxoG in the genome has been implicated in various observed in the promoter regions of genes such as E-cadherin inflammatory
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