Hypersensitivity to DNA-Damaging Agents in Abiotrophies: A New Explanation for Degeneration of Neurons, Photoreceptors, and Muscle in Alzheimer, Parkinson and Huntington Diseases, Retinitis Pigmentosa, and Duchenne Muscular Dystrophy

Robbins, Jay H.; Brumback, Roger A.; Polinsky, Ronald J.; Wirtschafter, Jonathan D.; Tarone, Robert E.; Scudiero, Dominic A.; Otsuka, Fujio

doi:10.1007/978-1-4899-2218-2_20

Cited by 26 publications

(14 citation statements)

References 71 publications

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“…Like others (4,22), we found that MTL from undamaged DNA decreased with increasing donor age, consistent with the telomere hypothesis of aging (4,22 (19), who demonstrated a normal response to UV irradiation in cell lines from patients with Alzheimer disease, and by a study from our laboratory (C. Link, personal communication), which shows normal genespecific repair of UV-induced pyrimidine dimers in familial Alzheimer fibroblasts. However, decreased DNA repair of single-strand breaks has been reported in cells from familial, but not sporadic, Alzheimer disease patients after exposure to N-ethyl-N-nitrosourea (33).…”

Section: Resultssupporting

confidence: 68%

“…The efficiency of telomere repair is less than that of the endogenous gene dihydrofolate reductase (DHFR) but more than that of an inactive genomic region, the X chromosome-associated 754 region. We have also examined the change in telomeric repair with senescence by measuring repair (i) in fibroblasts from old and young donors; (ii) in Werner syndrome fibroblasts, a condition with clinical signs of premature aging; and (iii) in fibroblasts from a patient with Alzheimer disease, a neurodegenerative disorder that may be associated with deficiencies in the repair of certain types of DNA damage (19). Our results indicate that telomere repair appears to decline with aging.…”

mentioning

confidence: 99%

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DNA damage and repair in telomeres: relation to aging.

Kruk

Rampino²,

Bohr³

1995

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

299

198

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We have established a method for the detection of DNA damage and its repair in human telomeres, the natural ends of chromosomes which are necessary for replication and critical for chromosomal stability. We find that ultraviolet light-induced pyrimidine dimers in telomeric DNA are repaired less efficiently than endogenous genes but more efficiently than inactive, noncoding regions. We have also measured telomeric length, telomeric DNA damage, and its repair in relation to the progression of aging. Telomeres are shorter in fibroblasts from an old donor compared to fibroblasts from a young donor, shortest in cells from a patient with the progeroid disorder Werner syndrome, and relatively long in fibroblasts from a patient with Alzheimer disease. Telomeric DNA repair efficiency is lower in cells from an old donor than in cells from a young donor, normal in Alzheimer cells, and slightly lower in Werner cells. It is possible that this decline in telomeric repair with aging is of functional significance to an age-related decline in genomic stability.

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Section: Resultssupporting

confidence: 68%

mentioning

confidence: 99%

DNA damage and repair in telomeres: relation to aging.

Kruk

Rampino²,

Bohr³

1995

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

299

198

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“…It is probable that excessive ODLs are present in most of the nuclear genes after FCIR despite of a functioning repair mechanism in normal animals. The conditions resemble the presence of excessive ODLs, due to disease conditions [29], or repair deficit in humans [31,[34][35][36][37]. Therefore, transcription of immediately early genes with ODLs immediately during cerebral oxidative stress gives rise to aberrant or variant mRNA.…”

Section: Resultsmentioning

confidence: 99%

Neuronal NOS Inhibitor That Reduces Oxidative DNA Lesions and Neuronal Sensitivity Increases the Expression of Intact c-fos Transcripts after Brain Injury

Cui

Liu

2001

Journal of Biomedical Science

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In response to oxidative stress, the ischemic brain induces immediate early genes when its nuclear genes contain gene damage. Antioxidant that reduces gene damage also reduces cell death. To study the mechanism of neuronal sensitivity, we investigated the transcription of the c-fos gene after brain injury of the ischemia-reperfusion type using focal cerebral ischemia-reperfusion in Long-Evans hooded rats. We observed a significant (p < 0.01) increase in c-fos mRNA in the ischemic cortex immediately after brain injury. However, the c-fos transcript was sensitive to RNase A protection assay (RPA) upon reperfusion. The transcript became significantly resistant to RPA (42%, p < 0.03) when 3-bromo-7-nitroindazole (25 mg/kg, i.p.), known to abolish nitric oxide, gene damage and neuronal sensitivity, was injected. Our data suggest that neuronal nitric oxide synthase and aberrant mRNA from genes with oxidative damage could be associated with neuronal sensitivity.

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“…Although genetic defects in the repair mechanisms of DNA have not yet been systematically observed in MS (Kuhlmann et al 2002) they have been found in other autoimmune diseases such as lupus erythematosus and rheumatoid arthritis (Harris et al 1982, Golan et al 1991, McCurdy et al 1997 as well as in several disorders of the nervous system (Robbins et al 1985). Increased spontaneous frequencies of chromosomal aberrations in peripheral blood lymphocytes (PBL) of MS patients have been reported (Seshadri et al 1983, Gipps and Kidsan 1984, Kä rki et al 1986, Senécal-Quevillon et al 1986).…”

Section: Introductionmentioning

confidence: 93%