Alcohol Induces DNA Damage and the Fanconi Anemia D2 Protein Implicating FANCD2 in the DNA Damage Response Pathways in Brain

Rulten, Stuart L.; Hodder, Ella; Ripley, Tamzin; Stephens, David; Mayne, Lynne

doi:10.1111/j.1530-0277.2008.00673.x

Cited by 26 publications

(30 citation statements)

References 54 publications

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“…In apparent contrast to our findings, a recent publication [43] showed that ethanol increased the expression of FANCD2 mRNA in the rat brain, and both ethanol and AA increased the amount of FANCD2 protein but did not stimulate FANCD2 monoubiquitination in brain cells. This is an interesting finding but is not directly relevant to our results with replicating cells, in contrast to neuronal cells, which are terminally differentiated.…”

Section: Discussioncontrasting

confidence: 99%

Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: Implications for alcohol-related carcinogenesis

Marietta

Thompson

Lamerdin

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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According to a recent IARC Working Group report, alcohol consumption is causally related to an increased risk of cancer of the upper aerodigestive tract, liver, colorectum, and female breast (Lancet Oncol. 2007 8:292-3). Several lines of evidence indicate that acetaldehyde (AA), the first product of alcohol metabolism, plays a very important role in alcohol-related carcinogenesis, particularly in the esophagus. We previously proposed a model for alcohol-related carcinogenesis in which AA, generated from alcohol metabolism, reacts in cells to generate DNA lesions that form interstrand crosslinks (ICLs) (Nucleic Acids Res. 2005 33:3513-20). Since the Fanconi anemia-breast cancer associated (FANC-BRCA) DNA damage response network plays a crucial role in protecting cells against ICLs, in the present work we tested this hypothesis by exposing cells to AA and monitoring activation of this network. We found that AA exposure results in a concentration-dependent increase in FANCD2 monoubiquitination, which is dependent upon the FANC core complex. AA also stimulated BRCA1 phosphorylation at Ser1524 and increased the level of γH2AX, with both modifications occurring in a dose-dependent manner. However, AA did not detectably increase the levels of hyperphosphorylated RPA34, a marker of single-stranded DNA exposure at replication forks. These results provide the initial description of the AA-DNA damage response, which is qualitatively similar to the cellular response to mitomycin C, a known DNA crosslinking agent. We discuss the mechanistic implications of these results, as well as their possible relationship to alcoholrelated carcinogenesis in different human tissues.

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Section: Discussioncontrasting

confidence: 99%

Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: Implications for alcohol-related carcinogenesis

Marietta

Thompson

Lamerdin

et al. 2009

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…Since maintaining genomic integrity is critical to preventing human pathologies such as premature aging, cancer, and neurodegeneration (Lieber 2010;McKinnon 2009;Rass et al 2007) the ethanol-induced defective DNA repair reported here may be an essential component of ethanol neurotoxicity. Moreover, our results are consistent with previous studies showing that ethanol causes oxidative damage to DNA (Cherian et al 2008;Chu et al 2007;Lamarche et al 2004;Rulten et al 2008), which may generate DSBs.…”

Section: Discussionsupporting

confidence: 95%

Chronic Alcohol Exposure Decreases 53BP1 Protein Levels Leading to a Defective DNA Repair in Cultured Primary Cortical Neurons

et al. 2015

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Chronic alcohol consumption may cause neurodevelopmental and neurodegenerative disorders. Alcohol neurotoxicity is associated with the production of acetaldehyde and reactive oxygen species that induce oxidative DNA damage. However, the molecular mechanisms by which ethanol disturbs the DNA damage response (DDR), resulting in a defective DNA repair, remain unknown. Here, we have used cultured primary cortical neurons exposed to 50 or 100 mM ethanol for 7 days to analyze the ethanol-induced DDR. Ethanol exposure produced a dose-dependent generation of double strand breaks and the formation of DNA damage foci immunoreactive for the histone γH2AX, a DNA damage marker, and for the ubiquitylated H2A, which is involved in chromatin remodeling at DNA damage sites. Importantly, these DNA damage foci failed to recruit the protein 53BP1, a crucial DNA repair factor. This effect was associated with a drop in 53BP1 mRNA and protein levels and with an inhibition of global transcription. Moreover, ethanol-exposed neurons treated with ionizing radiation (2 Gy) also failed to recruit 53BP1 at DNA damage foci and exhibited a greater vulnerability to DNA lesions than irradiated control neurons. Our results support that defective DNA repair, mediated by the deficient expression and recruitment of 53BP1 to DNA damage sites, represents a novel mechanism involved in ethanol neurotoxicity. The design of therapeutic strategies that increase or stabilize 53BP1 levels might potentially promote DNA repair and partially compensate alcohol neurotoxicity.

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“…The effect of alcohol can be modulated by polymorphisms in genes encoding enzymes for ethanol metabolism (alcohol dehydrogenases, aldehyde dehydrogenases, and cytochrome P450 2E1), folate metabolism, and DNA repair [29, 30]. Alcohol consumption is increasing in many countries and is an important cause of cancer worldwide [31].…”

Section: Discussionmentioning

confidence: 99%

Polymorphism of the DNA repair genes RAD51 and XRCC2 in smoking- and drinking-related laryngeal cancer in a Polish population

Romanowicz-Makowska¹,

Smolarz²,

Gajęcka³

et al. 2012

aoms

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IntroductionCigarette smoke and alcohol can generate reactive oxygen species, which may induce DNA double-strand breaks (DSBs), the most serious DNA lesion. In humans, DSBs are repaired mainly by non-homologous end joining and homologous recombination repair (HRR). Several polymorphisms in the DNA repair gene have been extensively studied in the association with various human cancers. In the present work we investigated the association between polymorphisms of two HRR genes, XRCC2 and RAD51, and tobacco- and alcohol-related larynx cancer in a Polish population.Material and methodsTwo polymorphisms of the XRCC2 gene, –41657C > T (rs718282) and 31479G > A (rs3218536), as well as one polymorphism of the RAD51 gene, –135G > C (rs1801320), were investigated by PCR-RFLP in 253 patients with larynx cancer and 253 age- and sex-matched non-cancer controls.ResultsAnalysis of the gene-smoking and -drinking interactions revealed a weak association between larynx cancer and the –41657C > T polymorphisms of the XRCC2 gene among the moderate alcohol drinkers. The C allele of the –135G > C polymorphism of RAD51 increased cancer risk in the smoker group. Increased risk was also found for heavy drinkers. Additionally, there were no significant differences between distributions of genotypes in subgroups assigned to different TNM stages and grades.ConclusionsThe results indicated that the –135G > C polymorphism of the RAD51 gene may be associated with smoking- and drinking-related larynx cancer in Poland.

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Alcohol Induces DNA Damage and the Fanconi Anemia D2 Protein Implicating FANCD2 in the DNA Damage Response Pathways in Brain

Cited by 26 publications

References 54 publications

Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: Implications for alcohol-related carcinogenesis

Acetaldehyde stimulates FANCD2 monoubiquitination, H2AX phosphorylation, and BRCA1 phosphorylation in human cells in vitro: Implications for alcohol-related carcinogenesis

Chronic Alcohol Exposure Decreases 53BP1 Protein Levels Leading to a Defective DNA Repair in Cultured Primary Cortical Neurons

Polymorphism of the DNA repair genes RAD51 and XRCC2 in smoking- and drinking-related laryngeal cancer in a Polish population

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