Critical Roles for Polymerase ζ in Cellular Tolerance to Nitric Oxide–Induced DNA Damage

Wu, Xiaohua; Takenaka, Kazumasa; Sonoda, Eiichiro; Hochegger, Helfrid; Kawanishi, Shosuke; Kawamoto, Takuo; Takeda, Shunichi; Yamazoe, Mitsuyoshi

doi:10.1158/0008-5472.can-05-2884

Cited by 46 publications

(30 citation statements)

References 57 publications

(72 reference statements)

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“…(52) G→T transversions can also occur via the preferential incorporation of adenine (32) Translesion DNA synthesis past an apurinic site by DNA polymerase ζ may also contribute to point mutations. (53) These findings suggest that 8-nitroguanine is a mutagenic lesion, leading to carcinogenesis. In a similar manner, 8-oxodG can also cause G→T transversions.…”

Section: Discussionmentioning

confidence: 97%

Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

Hiraku¹,

Tabata

et al. 2007

Cancer Science

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Recently, it was proposed that inflammation plays an integral role in the development of human papilloma virus (HPV)-induced cervical cancer. The present study sought to examine if 8-nitroguanine, a mutagenic nitrative DNA lesion formed during inflammation, contributes to cervical carcinogenesis. We obtained biopsy specimens from 30 patients with cervical intraepithelial neoplasia (CIN)1 (n = 9), CIN2 (n = 10), CIN3 (n = 6) and condyloma acuminatum (n = 5). We used immunohistochemistry to detect the formation of 8-nitroguanine and 8-oxo-7,8-dihydro-2′ ′ ′ ′-deoxyguanosine (8-oxodG), an oxidative DNA lesion, and compared it with the expression of the cyclindependent kinase inhibitor p16, which is considered to be a biomarker for cervical neoplasia. Double immunofluorescence labeling revealed that 8-nitroguanine and 8-oxodG were colocalized in cervical epithelial cells. Samples from CIN2-3 patients, most of whom were infected with high-risk HPV subtypes, exhibited significantly more intense staining for 8-nitroguanine than those with condyloma acuminatum. 8-Nitroguanine and 8-oxodG immunoreactivities correlated significantly with the CIN grade. We observed the expression of inducible nitric oxide synthase in epithelial and inflammatory cells from CIN lesions. Proliferating cell nuclear antigen was expressed specifically in dysplastic epithelial cells, but not in those of condyloma acuminatum. There were no statistically significant differences in p16 expression between CIN and condyloma acuminatum samples. These results suggest that high-risk HPV types promote inducible nitric oxide synthase-dependent DNA damage, which leads to dysplastic changes and carcinogenesis; in contrast, p16 appears to be merely a marker of HPV infection. Thus, 8-nitroguanine is a more suitable and promising biomarker for evaluating the risk of inflammation-mediated cervical carcinogenesis than p16. (Cancer Sci 2007; 98: 964-972) C ervical cancer is the second most common cancer among women worldwide, being the most common cancer among women in many regions of developing countries.(1) Molecular epidemiological studies have demonstrated that specific subtypes of HPV are associated with cervical cancer.(2-7) HPV DNA is detectable in greater than 90% of patients with cervical cancer. (3,5,7) The International Agency for Research on Cancer has determined that HPV-16 and HPV-18 are carcinogenic to humans (group 1) and that some other types of HPV are probably or possibly carcinogenic.(2) HPV infection is a necessary event preceding the development of premalignant lesions in the cervical epithelium, referred to as CIN or dysplasia, which can partially progress to cancer.(8) The mechanisms of HPV-induced cervical carcinogenesis, however, are not fully understood. Recently, the chronic inflammation induced by infection has been suggested as an important risk factor of various cancers.(9) Epidemiological studies have revealed that cervical inflammation in women infected with HPV is associated with cervical neoplasia, (8,10) although it is still unc...

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Section: Discussionmentioning

confidence: 97%

Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

Hiraku¹,

Tabata

et al. 2007

Cancer Science

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“…Should high rates of replication error among these lesions also be found to occur in mammalian cells, it may prove therapeutic to inhibit the activity of the offending DNA polymerase. In fact, recent work shows that elimination of pol dramatically increases the sensitivity of cells to killing by molecules that generate ⅐ NO (69). Inhibiting the bypass of oxidative DNA lesions could allow more time for repair processes such as base excision repair or recombination to occur.…”

Section: Discussionmentioning

confidence: 99%

DNA Polymerase V Allows Bypass of Toxic Guanine Oxidation Products in Vivo

Neeley

Delaney

Alekseyev

et al. 2007

Journal of Biological Chemistry

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Reactive oxygen and nitrogen radicals produced during metabolic processes, such as respiration and inflammation, combine with DNA to form many lesions primarily at guanine sites. Understanding the roles of the polymerases responsible for the processing of these products to mutations could illuminate molecular mechanisms that correlate oxidative stress with cancer. Using M13 viral genomes engineered to contain single DNA lesions and Escherichia coli strains with specific polymerase (pol) knockouts, we show that pol V is required for efficient bypass of structurally diverse, highly mutagenic guanine oxidation products in vivo. We also find that pol IV participates in the bypass of two spiroiminodihydantoin lesions. Furthermore, we report that one lesion, 5-guanidino-4-nitroimidazole, is a substrate for multiple SOS polymerases, whereby pol II is necessary for error-free replication and pol V for error-prone replication past this lesion. The results spotlight a major role for pol V and minor roles for pol II and pol IV in the mechanism of guanine oxidation mutagenesis.The genome is continually damaged by spontaneously generated and environmental chemical agents. Many of the lesions formed in DNA strongly inhibit replicative polymerases. If repair of these lesions fails or is not fast enough, cells can biochemically adapt to "tolerate" the toxic DNA lesions, as evidenced by replication of the damaged DNA (1). Human cells possess at least 15 DNA polymerases, including 5 that are referred to as translesion synthesis (TLS) 3 polymerases and are specifically involved in the replication of damaged DNA. Four of these enzymes, pol , pol , pol , and REV1, belong to the Y family of DNA polymerases, whereas pol belongs to the B family (2). Escherichia coli possess three polymerases, pol II, pol IV, and pol V, whose expression levels are up-regulated in response to DNA damage. Extensive research on the structure and function of these polymerases and their homologues suggests that these polymerases allow replication to progress in the presence of DNA lesions that are strongly inhibitory to the replicative polymerase, pol III (1). The presence of the three SOSinducible polymerases allows E. coli to be used as a model system for DNA replication past damage products.pol II (pol B) (3) is a B family DNA polymerase and has 3Ј 3 5Ј-exonuclease activity. Consequently, this enzyme replicates normal DNA with high fidelity and has an error rate less of than 10 Ϫ6 (4). pol II participates in error-free replication restart (5, 6) and can also carry out TLS past abasic sites (3, 7), 3,N 4 -ethenocytosine (8), and N-(deoxyguanosin-8-yl)-2-acetylaminofluorene (9). pol IV (DinB) (10) and pol V (UmuD 2 ЈC) (11) are members of the Y family of DNA polymerases, which have less sterically restrictive active sites than normal replicative polymerases (12) and lack exonuclease activity (1). The error rates of these polymerases are much higher than the other E. coli polymerases and are on the order of 10 Ϫ4 to 10 Ϫ5 for pol IV (13) and 10 Ϫ3 to 10 Ϫ4...

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“…BMV was shown to present glycoproteins as L-amino acid oxidase (Ribeiro et al, 2007), which catalyzes the oxidative deamination of L-amino acids, producing a-keto acids, ammonia, and hydrogen peroxide, the latter being an important mediator of oxidative stress and a potent mutagen (Konat, 2003). BMVinduced inflammatory mediators, such as nitric oxide (NO) might also be responsible for the genotoxic effect herein observed, since NO reacts with superoxide or oxygen, producing deleterious effects on DNA (Wu et al, 2006). BMV metalloproteinases may also be involved.…”

Section: Discussionmentioning

confidence: 98%

In vitroandin vivogenotoxic evaluation ofBothrops moojenisnake venom

Zobiole

Caon

Bertól

et al. 2014

Pharmaceutical Biology

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Context: Bothrops moojeni Hoge (Viperidae) venom is a complex mixture of compounds with therapeutic potential that has been included in the research and development of new drugs. Along with the biological activity, the pharmaceutical applicability of this venom depends on its toxicological profile. Objective: This study evaluates the cytotoxicity and genotoxicity of the Bothrops moojeni venom (BMV). Material and methods: The in vitro cytotoxicity and genotoxicity of a pooled sample of BMV was assessed by the MTT and Comet assay, respectively. Genotoxicity was also evaluated in vivo through the micronucleus assay. Results: BMV displayed a 50% cytotoxic concentration (CC 50 ) on Vero cells of 4.09 mg/mL. Vero cells treated with 4 mg/mL for 90 min and 6 h presented significant (p50.05, ANOVA/NewmanKeuls test) higher DNA damage than the negative control in the Comet assay. The lower DNA damage found after 6 h compared with the 90 min treatment suggests a DNA repair effect. Mice intraperitoneally treated with BMV at 10, 30, or 80 mg/animal presented significant genotoxicity (p50.05, ANOVA/Newman-Keuls test) in relation to the negative control after 24 h of treatment. Contrary to the in vitro results, no DNA repair seemed to occur in vivo up to 96 h post-venom inoculation at a dose of 30 mg/animal. Discussion and conclusion: The results show that BMV presents cyto-and genotoxicity depending on the concentration/dose used. These findings emphasize the importance of toxicological studies, including assessment of genotoxicity, in the biological activity research of BMV and/or in the development of BMV-derived products.

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Critical Roles for Polymerase ζ in Cellular Tolerance to Nitric Oxide–Induced DNA Damage

Cited by 46 publications

References 57 publications

Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

Nitrative and oxidative DNA damage in cervical intraepithelial neoplasia associated with human papilloma virus infection

DNA Polymerase V Allows Bypass of Toxic Guanine Oxidation Products in Vivo

In vitroandin vivogenotoxic evaluation ofBothrops moojenisnake venom

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