Uracil DNA Glycosylase Counteracts APOBEC3G-Induced Hypermutation of Hepatitis B Viral Genomes: Excision Repair of Covalently Closed Circular DNA

Kitamura, Koichi; Wang, Zhe; Chowdhury, Sajeda; Simadu, Miyuki; Koura, Miki; Muramatsu, Masamichi

doi:10.1371/journal.ppat.1003361

Cited by 62 publications

(100 citation statements)

References 70 publications

(137 reference statements)

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“…DNA fragments encoding human A3A and A3F were generated by reverse transcription-PCR (RT-PCR) using primers A3A fwd, 5=-ATAGAATTCATGGAAGCCAGCCCAGC-3=, A3A rev, 5=-ATAT CTCGAGTCAGTTCCCTGATTCT-3=, A3F fwd, 5=-ATTTAAGCTTATG AAGCCTCACTTCAG-3=, and A3F rev, 5=-AATTCTCGAGTCATTCGA GAATCTCCTGCAG-3=, and inserted into a multiple cloning site of pcDNA3Tag1A (Invitrogen) to make FLAG-tagged A3A and A3F expression vectors, respectively. The A3G nontagged protein expression vector was made by deletion of FLAG region from pFlag-A3G (37). Differential DNA denaturation PCR (3D-PCR) control vectors were generated by cloning PCR fragments into the pGEM-T Easy vector (Promega).…”

Section: Methodsmentioning

confidence: 99%

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APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Wang

Wakae

Kitamura

et al. 2014

J Virol

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101

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A polipoprotein B mRNA-editing catalytic polypeptide (APOBEC) proteins are a family of proteins that share cytidine deaminase activity of DNA and RNA. In humans, the APOBEC family is composed of at least 11 members, including activation-induced cytidine deaminase (AID) and APOBEC1, -2, -3A, -3B, -3C, -3DE, -3F, -3G, -3H, and -4 (1, 2). AID introduces cytidine (C)-to-uracil (U) conversion in immunoglobulin (Ig) genes, a step that is further catalyzed by downstream DNA repair machineries, including base excision repair (BER), mismatch repair, and nonhomologous end-joining repair, to trigger somatic hypermutation, class switch recombination, gene conversion, and chromosomal translocation (3-6). AID also introduces mutations in non-Ig gene loci, such as c-Myc and Bcl-6, although less frequently than in Ig genes (3, 7). Recent studies have suggested that APOBEC3 protein (A3) deaminase activity is responsible for a novel type of mutations called kataegis in multiple human cancers, including cancers of the bladder, cervix, lung, head and neck, and breast (8-13).A3s are antiviral factors against viruses and transposable elements that use reverse transcription during their life cycle (1, 2, 14-16). The antiviral functions of A3s have been extensively studied for human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). APOBEC3G (A3G) physically associates with viral RNP complexes, including viral genomic RNA, gag protein (in the case of HIV-1), and P and core protein (in the case of HBV), and is encapsidated into a nucleocapsid, thereby inhibiting reverse transcription in infected cells (2,14,17). Moreover, A3G-induced hypermutation in viral DNA leads to inhibition of HIV-1 replication by either BER-mediated DNA degradation or accumulation of destructive mutations in the viral genome (16,(18)(19)(20). How C-to-U conversion in cellular or viral DNA is converted into different genetic alterations (hypermutation, recombination, and DNA degradation) remains unknown.Human papillomaviruses (HPVs) are small double-stranded DNA viruses infecting epithelial cells. A subset of mucosal HPVs is recognized as a causative agent of cervical cancer (21, 22), among which HPV16 accounts for at least 50% of cervical cancer cases worldwide (23). The HPV16 genome is a 7.9-kb closed circular DNA and is composed of at least 8 open reading frames (E1, E2, E4, E5, E6, E7, L1, and L2) as well as the noncoding long control region (LCR). LCR contains the replication origin and the P 97 promoter responsible for transcription of the E6 and E7 genes. E6 and E7 are viral oncoproteins that degrade p53 and retinoblastoma proteins, respectively, and their enhanced expression is required for cellular transformation (22). In its normal life cycle, HPV16 infects the basal cells of cervical epithelia and establishes their genomes as extrachromosomal episomes. In invasive cervical cancer, however, the viral DNA is frequently integrated into the host chromosome, which generally leads to constitutive expression of E6 and E7. The viral DNA integrat...

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Section: Methodsmentioning

confidence: 99%

“…All the plasmids used in this study were sequenced at least once to verify them. Other plasmids used in this study have been described previously (37,40).…”

Section: Methodsmentioning

confidence: 99%

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APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Wang

Wakae

Kitamura

et al. 2014

J Virol

Self Cite

101

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“…This modified HBV DNA is susceptible to degradation, or alternatively, numerous G-to-A nucleotide mutations are incorporated into positive-strand viral DNA [99,105] . This process is counteracted by UNG [106] . Accordingly, APOBECs family members can also increase somatic mutations to a threshold that exceeds the host's repair ability, thus initiating the cancer evolutionary process.…”

Section: Apobecs Bridge Inflammation and Cancermentioning

confidence: 99%

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

Cao¹

2017

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How to cite this article: Cao GW. Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis. Hepatoma Res 2017;3:241-59.Non-resolving inflammation, which may be maintained by infection, pollution, and metabolic stimulants and their interactions with immunogenetic predisposition, provides a fertile field for cancer development. This is strongly evident in hepatocellular carcinoma. Here, the framework of a hypothesis called Cancer Evo-Dev is presented, based on the advances in hepatitis B virusinduced hepatocarcinogenesis. Several aspects central to this theory are as follows: (1) immune imbalance caused by the interaction of immunogenetic predispositions and hepatitis B virus infection maintains non-resolving inflammation; (2) active inflammation executants promote mutations in viral and host genomes via disbalancing mutagenic forces including cytidine deaminases and mutation-repairing forces including uracil-DNA glycosylases, thus promoting cancer-related somatic mutations and viral mutations; (3) a small percentage of the cells whose somatic mutations alter the survival signalling adapt to the inflammatory microenvironment, de-differentiate via demethylating role of cytidine deaminases, and reversely develop into tumor-initiating cells (TICs); (4) under the cultivation of some factors like POSTN from tumorinfiltrating fibroblasts and M2 macrophages, TICs acquire the stemness, cancer-stem cells obtain distinct metastatic and drug-resistant potentials under the selection pressure from distinct microenvironments; (5) glycolysis persistence in the presence of oxygen provides essential energy for cell survival and the raw material for DNA synthesis. Thus, cancer development is characterized by an evolutionary process of "mutation-selection-adaptation". The framework of Cancer Evo-Dev can be verified in other cancers. Cancer Evo-Dev lays theoretical foundation for understanding the mechanisms by which inflammation promotes cancer development, and it also plays a role in specific prophylaxis, prediction, and targeted treatment of cancers. Key words:Inflammation, hepatitis B virus, mutations, hepatoma, Cancer Evo-Dev ABSTRACTArticle history:

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“…First, as multiple APOBEC3 family members have now been shown to target a number of different HBV DNA replication forms, it will be important to understand the specificity and nature of these interactions. In particular, compared to cccDNA, the precursor single-stranded and partially double-stranded relaxed circular (RC) DNA forms would appear to be more efficient substrates for deamination, 16 as APOBEC3 acts exclusively on single-stranded DNA. RC DNA deamination could therefore also contribute to cccDNA loss and inhibition of HBV replication.…”

Section: Commentmentioning

confidence: 99%

Cytidine deamination and cccDNA degradation: A new approach for curing HBV?

Ding

Robek

2014

Hepatology

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Current antiviral agents can control but not eliminate hepatitis B virus (HBV), because HBV establishes a stable nuclear covalently closed circular DNA (cccDNA). Interferon-a treatment can clear HBV but is limited by systemic side effects. We describe how interferon-a can induce specific degradation of the nuclear viral DNA without hepatotoxicity and propose lymphotoxin-b receptor activation as a therapeutic alternative. Interferon-a and lymphotoxin-b receptor activation upregulated APOBEC3A and APOBEC3B cytidine deaminases, respectively, in HBV-infected cells, primary hepatocytes, and human liver needle biopsies. HBV core protein mediated the interaction with nuclear cccDNA, resulting in cytidine deamination, apurinic/apyrimidinic site formation, and finally cccDNA degradation that prevented HBV reactivation. Genomic DNA was not affected. Thus, inducing nuclear deaminases-for example, by lymphotoxin-b receptor activationallows the development of new therapeutics that, in combination with existing antivirals, may cure hepatitis B. CommentChronic hepatitis B virus (HBV) infection is a leading cause of severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). Current treatments for chronic HBV infection are suboptimal and rarely eliminate the virus, as they do not effectively remove episomal HBV covalently closed circular DNA (cccDNA) from the nuclei of infected hepatocytes. Therefore, there is a need for new therapeutic alternatives that specifically and potently eradicate cccDNA with minimal side effects.It has long been noted that cytokines including tumor necrosis factor (TNF)-a and interferon (IFN)-c play a critical role in clearing HBV replicative intermediates, including cccDNA, from hepatocytes in a noncytopathic manner.

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Uracil DNA Glycosylase Counteracts APOBEC3G-Induced Hypermutation of Hepatitis B Viral Genomes: Excision Repair of Covalently Closed Circular DNA

Cited by 62 publications

References 70 publications

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

APOBEC3 Deaminases Induce Hypermutation in Human Papillomavirus 16 DNA upon Beta Interferon Stimulation

Cancer Evo-Dev, a novel hypothesis derived from studies on hepatitis B virus-induced carcinogenesis

Cytidine deamination and cccDNA degradation: A new approach for curing HBV?

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