Suicidal function of DNA methylation in age-related genome disintegration

Mazin, A L

doi:10.1016/j.arr.2009.04.005

Cited by 29 publications

(17 citation statements)

References 168 publications

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“…Hypermethylation may cause heterochromatinization and, thus, result in gene silencing (Mazin 1994(Mazin , 2009. It was demonstrated that progressive heterochromatinization of chromosomes (condensation of eu-and heterochromatic regions) occurs during aging, followed by inactivation of the genes that functioned actively at younger ages (Lezhava 2001(Lezhava , 2006.…”

Section: Discussionmentioning

confidence: 99%

Remodeling of heterochromatin induced by heavy metals in extreme old age

Lezhava

Monaselidze

Jokhadze

et al. 2010

AGE

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The levels of chromosome instability and heat absorption of chromatin have been studied in cultured lymphocytes derived from blood of 80-93-and 18-30-year-old individuals, under the effect of heavy metal Cu(II) and Cd(II) salts. The analysis of the results obtained indicates that 50 μM Cu(II) induced a significantly higher level of cells with chromosome aberrations in old donors (13.8±1.5% vs control, 3.8±1.7%), whereas treatment with 100 μM Cd(II) did not induce any changes in the background index. Analysis of the lymphocyte melting curves showed that Cu(II) ions caused more effective condensation of heterochromatin in old healthy individuals compared with young donors, which was expressed by the increase of the T m of elderly chromatin by~3°C compared with the norm. Treatment of lymphocyte chromatin of old individuals with 100 μM Cd(II) caused decondensation (deheterochromatinization) of both the facultative and constitutive domains of heterochromatin. The deheterochromatinization T m was decreased by~3-3.5°C compared with the T m observed for young individuals. Thus, the chromatin of cultured lymphocytes from the old-aged individuals underwent modification under the influence of copper and cadmium salts. Cu(II) caused additional heterochromatinization of heterochromatin, and Cd(II) caused deheterochromatinization of facultative and constitutive heterochromatin. Our data may be important as new information on the remodeling of constitutive and facultative heterochromatin induced by heavy metals in aging, aging pathology, and pathology linked with metal ions.

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Section: Discussionmentioning

confidence: 99%

Remodeling of heterochromatin induced by heavy metals in extreme old age

Lezhava

Monaselidze

Jokhadze

et al. 2010

AGE

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“…1) [26][27][28][29]. There are~3×10 7 residues of 5mC in the mammalian genome [28], but 5mC content in the genome varies more than 100-fold across species [30]. Generally, when DNA methylation is involved in gene silencing, the 5mCs are located in cytosine-phosphate-guanine (CpG) dinucleotides (the phosphate is the phosphodiester bond between the cytosine and guanine nucleotides) within the 5' regulatory regions of genes upstream from the transcriptional start sites [20,31,32].…”

Section: Dna Methylation As An Epigenetic Mechanismmentioning

confidence: 99%

“…The methylation of cytosines causes spontaneous mutations in the genome [30]. CG methylation sites are hotspots for most C>T and G>A transition mutations in the human genome.…”

Section: Dna Methylation As An Epigenetic Mechanismmentioning

confidence: 99%

“…CG methylation sites are hotspots for most C>T and G>A transition mutations in the human genome. Age-related accumulation of 5mC-triggered mutations in tumor suppressor genes, cell cycle genes, and oncogenes is a major pathway for developing cancer, accounting for about 60 % of all spontaneous somatic mutations that inactivate the human p53 gene [30]. Thus, DNA methylation has been considered a basic mechanism for aging because it destabilizes the genome and organismal function over time [30].…”

Section: Dna Methylation As An Epigenetic Mechanismmentioning

confidence: 99%

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Aberrant Regulation of DNA Methylation in Amyotrophic Lateral Sclerosis: A New Target of Disease Mechanisms

Martin

Wong

2013

Neurotherapeutics

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Amyotrophic lateral sclerosis (ALS) is the third most common adult-onset neurodegenerative disease. A diagnosis is fatal owing to degeneration of motor neurons in brain and spinal cord that control swallowing, breathing, and movement. ALS can be inherited, but most cases are not associated with a family history of the disease. The mechanisms causing motor neuron death in ALS are still unknown. Given the suspected complex interplay between multiple genes, the environment, metabolism, and lifestyle in the pathogenesis of ALS, we have hypothesized that the mechanisms of disease in ALS involve epigenetic contributions that can drive motor neuron degeneration. DNA methylation is an epigenetic mechanism for gene regulation engaged by DNA methyltransferase (Dnmt)-catalyzed methyl group transfer to carbon-5 in cytosine residues in gene regulatory promoter and nonpromoter regions. Recent genome-wide analyses have found differential gene methylation in human ALS. Neuropathologic assessments have revealed that motor neurons in human ALS show significant abnormalities in Dnmt1, Dnmt3a, and 5-methylcytosine. Similar changes are seen in mice with motor neuron degeneration, and Dnmt3a was found abundantly at synapses and in mitochondria. During apoptosis of cultured motor neuron-like cells, Dnmt1 and Dnmt3a protein levels increase, and 5-methylcytosine accumulates. Enforced expression of Dnmt3a, but not Dnmt1, induces degeneration of cultured neurons. Truncation mutation of the Dnmt3a catalytic domain and Dnmt3a RNAi blocks apoptosis of cultured neurons. Inhibition of Dnmt catalytic activity with small molecules RG108 and procainamide protects motor neurons from excessive DNA methylation and apoptosis in cell culture and in a mouse model of ALS. Thus, motor neurons can engage epigenetic mechanisms to cause their degeneration, involving Dnmts and increased DNA methylation. Aberrant DNA methylation in vulnerable cells is a new direction for discovering mechanisms of ALS pathogenesis that could be relevant to new disease target identification and therapies for ALS.

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“…Due to 5-methylcytosine's spontaneous or enzymatic conversion to thymine, the CpG sites are only 5-10% of their predicted frequency in mammalian genomes, as a result of its progressive elimination due to its high mutation rates (Gardiner-Garden and Frommer, 1987;Cross et al, 1994). About 70-80% of genomic CpG sites are methylated in most vertebrates, including humans (Ehrlich, 1982;Antequera andBird, 1993, 1994;Bird, 1995;Mazin, 2009).…”

Section: Dna Substratementioning

confidence: 99%