Misincorporation of Uracil Into DNA as Possible Contributor to Neuronal aging and Abiotrophy

Mazzarello, Paolo; Focher, Federico; Verri, Annalisa; Spadari, Silvio

doi:10.3109/00207459008987169

Cited by 17 publications

(10 citation statements)

References 30 publications

(18 reference statements)

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“…Uracil accumulates in DNA as a result of spontaneous deamination of cytosine (23), generating a U:G mismatch; or incorporation of dUMP during replication (24), which results in a U:A base pair. UDG activity decreases rapidly during neuronal development and remains at a low level in adult neurons (25), suggesting that uracil might accumulate in DNA of adult neurons and contribute to neuronal aging (26). Furthermore, a recent study reported that suppression of UDG expression induced apoptosis in cultured rat hippocampal neurons (27), supporting a role for this enzyme in maintaining neuronal viability.…”

Section: Discussionmentioning

confidence: 99%

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Weissman

Sorensen

et al. 2007

Nucleic Acids Research

270

229

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Oxidative stress is thought to play a role in the pathogenesis of Alzheimer's disease (AD) and increased oxidative DNA damage has been observed in brain tissue from AD patients. Base excision repair (BER) is the primary DNA repair pathway for small base modifications such as alkylation, deamination and oxidation. In this study, we have investigated alterations in the BER capacity in brains of AD patients. We employed a set of functional assays to measure BER activities in brain tissue from short post-mortem interval autopsies of 10 sporadic AD patients and 10 age-matched controls. BER activities were also measured in brain samples from 9 amnestic mild cognitive impairment (MCI) subjects. We found significant BER deficiencies in brains of AD patients due to limited DNA base damage processing by DNA glycosylases and reduced DNA synthesis capacity by DNA polymerase β. The BER impairment was not restricted to damaged brain regions and was also detected in the brains of amnestic MCI patients, where it correlated with the abundance of neurofibrillary tangles. These findings suggest that BER dysfunction is a general feature of AD brains which could occur at the earliest stages of the disease. The results support the hypothesis that defective BER may play an important role in the progression of AD.

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Section: Discussionmentioning

confidence: 99%

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Weissman

Sorensen

et al. 2007

Nucleic Acids Research

270

229

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“…It is difficult to predict the outcome of such studies as little is known about the reversibility of the damage induced by folate deficiency. Uracil in DNA could contribute to the effects of both folate and B 12 deficiencies on brain function (61). Although deficiencies of folate or B 12 may not result in uracil misincorporation into genomic DNA of postmitotic neurons, this process could occur in the DNA of dividing glial cells (oligodendrocytes).…”

Section: Discussionmentioning

confidence: 99%

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage

Blount

Mack

Wehr

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

1,275

902

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Folate deficiency causes massive incorporation of uracil into human DNA (4 million per cell) and chromosome breaks. The likely mechanism is the deficient methylation of dUMP to dTMP and subsequent incorporation of uracil into DNA by DNA polymerase. During repair of uracil in DNA, transient nicks are formed; two opposing nicks could lead to chromosome breaks. Both high DNA uracil levels and elevated micronucleus frequency (a measure of chromosome breaks) are reversed by folate administration. A significant proportion of the U.S. population has low folate levels, in the range associated with elevated uracil misincorporation and chromosome breaks. Such breaks could contribute to the increased risk of cancer and cognitive defects associated with folate deficiency in humans.

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“…This misincorporation could happen when the cell is deficient in folate cofactors () or particularly when dTTP metabolism is inhibited by chemotherapy agents such as methotrexate or 5-fluorouracil ( , ). In addition, polymerase-mediated DNA repair can cause dUMP misincorporation, a problem of greater significance in neurons ( , ). The oxidation of the methyl group of thymine can generate 5-hydroxymethyluracil (HmU), one of the more frequent oxidation damage products found in DNA ( − ).…”

mentioning

confidence: 99%

Endogenous DNA Lesions Can Inhibit the Binding of the AP-1 (c-Jun) Transcription Factor

et al. 2002

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The repair of DNA damage, caused by both endogenous and exogenous sources, is necessary to remove lesions that either miscode or block DNA or RNA polymerases. We propose that damage also must be repaired to maintain sequence-specific DNA-protein interactions. In this paper, we have systematically studied two lesions that interfere with one important DNA landmark, the thymine methyl group. Oxidation of the thymine methyl group in DNA generates 5-hydroxymethyluracil (HmU) whereas the misincorporation of dUMP into DNA generates uracil (U), replacing the methyl group with a hydrogen. Both substitutions are shown to inhibit binding of the AP-1 (c-Jun) transcription factor. The energy cost of the perturbation, approximately 0.4 kcal/mol, is similar in magnitude for both U and HmU substitutions and is additive when multiple substitutions are present. A third lesion, substitution of the central C:G base pair of the AP-1 DNA binding domain with the pro-mutagenic U:G mispair, unexpectedly increases AP-1 binding, allowing the transcription factor to interfere with uracil DNA glycosylase activity. Our results support the hypothesis that an additional role for DNA repair systems is to maintain the integrity of sequence-specific DNA-protein interactions, a role of particular importance in long-lived organisms.

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Misincorporation of Uracil Into DNA as Possible Contributor to Neuronal aging and Abiotrophy

Cited by 17 publications

References 30 publications

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Defective DNA base excision repair in brain from individuals with Alzheimer's disease and amnestic mild cognitive impairment

Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: Implications for cancer and neuronal damage

Endogenous DNA Lesions Can Inhibit the Binding of the AP-1 (c-Jun) Transcription Factor

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