Singlet Oxygen induced mutation spectrum in mammalian cells

Biologia, Reginas Costa de; Riberio, Denise T.; Nigro, Rogério G.; Mascio, Paolo Di; Menck, Carlos Frederico Martins

doi:10.1093/nar/20.16.4319

Cited by 49 publications

(10 citation statements)

References 43 publications

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“…Moreover, the nucleotide transition of G:C to A:T or A:T to G:C and transversion of A:T to C:G were more prevalent in the AKR1B8 deficient mucosa. These changes are consistent with oxidative and carbonyl-induced DNA damage (10, 39). Therefore, the increased inflammatory cytokines and cellular and DNA damage induced by oxidative stress and lipid peroxides provide a mechanism for many of the events that drive the severity of UC and the progression of UC to cancer in this mouse model.…”

Section: Discussionsupporting

confidence: 83%

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Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

Shen

Yan

et al. 2015

Clinical Cancer Research

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Purpose Ulcerative colitis (UC) and colitis-associated colorectal cancer (CAC) is a serious health issue, but etiopathological factors remain unclear. Aldo-keto reductase 1B10 (AKR1B10) is specifically expressed in the colonic epithelium, but down-regulated in colorectal cancer. This study was aimed to investigate the etiopathogenic role of AKR1B10 in UC and CAC. Experimental design UC and CAC biopsies (paraffin-embedded sections) and frozen tissues were collected to examine AKR1B10 expression. Aldo-keto reductase 1B8 (the ortholog of human AKR1B10) knockout (AKR1B8 −/−) mice were produced to estimate its role in the susceptibility and severity of chronic colitis and associated dysplastic lesions, induced by dextran sulfate sodium (DSS) at a low dose (2%). Genome-wide Exome sequencing was used to profile DNA damage in DSS-induced colitis and tumors. Results AKR1B10 expression was markedly diminished in over 90% of UC and CAC tissues. AKR1B8 deficiency led to reduced lipid synthesis from butyrate and diminished proliferation of colonic epithelial cells. The DSS-treated AKR1B8 −/− mice demonstrated impaired injury repair of colonic epithelium and more severe bleeding, inflammation, and ulceration. These AKR1B8 −/− mice had more severe oxidative stress and DNA damage, and dysplasias were more frequent and at a higher grade in the AKR1B8 −/− mice than in wild type mice. Palpable masses were seen in the AKR1B8 −/− mice only, not in wild type. Conclusion AKR1B8 is a critical protein in the proliferation and injury repair of the colonic epithelium and in the pathogenesis of UC and CAC, being a new etiopathogenic factor of these diseases.

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Section: Discussionsupporting

confidence: 83%

“…In addition, nucleotide transition of G:C to A:T ( P < 0.05) or A:T to G:C ( P < 0.01) and transversion of A:T to C:G ( P < 0.05) were more prevalent in AKR1B8 −/− colitis and tumors compared to WT colits (Fig. 6C), consistent with the oxidative and carbonyl-induced DNA damage (10, 39). …”

Section: Resultssupporting

confidence: 66%

Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

Shen

Yan

et al. 2015

Clinical Cancer Research

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“…In addition, the mutagenesis spectrum of point mutations is compatible with oxidative stress-induced mutagenesis. Indeed, the strong increase in GC to CG transversions is a signature of oxidative damage by singlet oxygen 17 18 19 . In particular, the oxidation of 8-oxoguanine can form imidazolone, guanidinohydantoin or spiroiiminodihydantoin, which could be responsible for GC to CG transversions 20 .…”

Section: Discussionmentioning

confidence: 99%

A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis

Saintigny

Chevalier

Bravard

et al. 2016

Sci Rep

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Endogenous stress represents a major source of genome instability, but is in essence difficult to apprehend. Incorporation of labeled radionuclides into DNA constitutes a tractable model to analyze cellular responses to endogenous attacks. Here we show that incorporation of [3H]thymidine into CHO cells generates oxidative-induced mutagenesis, but, with a peak at low doses. Proteomic analysis showed that the cellular response differs between low and high levels of endogenous stress. In particular, these results confirmed the involvement of proteins implicated in redox homeostasis and DNA damage signaling pathways. Induced-mutagenesis was abolished by the anti-oxidant N-acetyl cysteine and plateaued, at high doses, upon exposure to L-buthionine sulfoximine, which represses cellular detoxification. The [3H]thymidine-induced mutation spectrum revealed mostly base substitutions, exhibiting a signature specific for low doses (GC > CG and AT > CG). Consistently, the enzymatic activity of the base excision repair protein APE-1 is induced at only medium or high doses. Collectively, the data reveal that a threshold of endogenous stress must be reached to trigger cellular detoxification and DNA repair programs; below this threshold, the consequences of endogenous stress escape cellular surveillance, leading to high levels of mutagenesis. Therefore, low doses of endogenous local stress can jeopardize genome integrity more efficiently than higher doses.

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“…Again, RB's potential for mutagenicity was not assessed [17]. Because RB can enter living cells and stain the nucleus, this raises questions about mutagenicity, especially since studies have demonstrated that byproducts of Rose Bengal are capable of interacting with and damaging DNA [18,19]. This study examines the cytotoxicity and mutagenicity associated with photoactivated RB in hopes of gaining a better insight into the potential hazards associated with the use of RB in PTB procedures.…”

Section: Introductionmentioning

confidence: 99%

Is the Photosuturing Agent, Rose Bengal, a Mutagen?

Hunter-Ellul¹,

Wang²,

Wickliffe³

et al. 2014

JCDSA

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Rose Bengal (RB) is a potential photosuturing agent that may improve standard dermatologic surgical closure techniques. However, RB produces reactive oxygen species with photoactivation and its photomutagenic potential must be considered in clinical application. We investigated cytotoxicity, mutagenicity, and singlet oxygen (SO) production of RB on epithelial Chinese hamster ovary cell line. Cells were exposed to RB concentrations: 0.1%, 0.01%, 0.001%, 0.0001%, 0.00001%; irradiated for 400 s using a high-intensity visible wavelength lamp or maintained in the dark. Cell viability was assessed by XTT assay, mutagenicity by HPRT gene mutation assay, and SO production by Sensor Green reagent. RB > 0.001% was significantly cytotoxic. Viabilities were uninfluenced by ≤0.0001% RB controls, or 30-min incubation. 49% of irradiated cells died after 24-h in 0.0001% RB. At ≥0.001% RB, >90% of cells died. Irradiating 0.00001%-0.001% RB increased SO; levels dropped significantly between 0.01%-0.1%. Controls exhibited negligible SO production. HPRT suggested that RB was not mutagenic (0.0001%, 0.00001%); SO induction increased between 0.00001%-0.001%, with reduced production at higher concentrations. Pilot studies suggested irradiated 0.0001% RB is mutagenic in vitro; current data suggest RB is not photomutagenic. The contribution of RB's cytotoxicity on observed clinical improvement of scars and mutagenic potential remains unclear, necessitating further study.

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Singlet Oxygen induced mutation spectrum in mammalian cells

Cited by 49 publications

References 43 publications

Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

Impaired Self-Renewal and Increased Colitis and Dysplastic Lesions in Colonic Mucosa of AKR1B8-Deficient Mice

A threshold of endogenous stress is required to engage cellular response to protect against mutagenesis

Is the Photosuturing Agent, Rose Bengal, a Mutagen?

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