Enzymology of DNA Replication and Repair in Brain

Kuenzle, Clive C.

doi:10.1007/978-1-4613-2321-1_18

Cited by 3 publications

(3 citation statements)

References 30 publications

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“…The present study indicates that "cycling neurons" (i.e., neurons that have a DNA content of Ͼ2n and at the same time express cyclin B1) are well in the range of ϳ20%, which is much higher than thought previously. Reasons for an incomplete replication of DNA could be an accumulation of DNA damage and a decreased expression and activity of replication enzymes (Kuenzle, 1985;Mazzarello et al, 1992;Lovell et al, 2000;Nouspikel and Hanawalt, 2003). Developmental deficiencies in chromosome segregation giving rise to aneuploid neuronal progenitors have also been suggested as a critical pathogenetic mechanism in AD (Potter, 1991).…”

Section: Discussionmentioning

confidence: 99%

Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

Mosch

Morawski²,

Mittag³

et al. 2007

Journal of Neuroscience

239

248

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Reactivation of the cell cycle, including DNA replication, might play a major role in Alzheimer's disease (AD). A more than diploid DNA content in differentiated neurons might alternatively result from chromosome mis-segregation during mitosis in neuronal progenitor cells. It was our objective to distinguish between these two mechanisms for aneuploidy and to provide evidence for a functional cell cycle in AD. Using slide-based cytometry, chromogenic in situ hybridization, and PCR amplification of alu-repeats, we quantified the DNA amount of identified cortical neurons in normal human brain and AD and analyzed the link between a tetraploid DNA content and expression of the early mitotic marker cyclin B1. In the normal brain, the number of neurons with a more than diploid content amounts to ϳ10%. Less than 1% of neurons contains a tetraploid DNA content. These neurons do not express cyclin B1, most likely representing constitutional tetraploidy. This population of cyclin B1-negative tetraploid neurons, at a reduced number, is also present in AD. In addition, a population of cyclin B1-positive tetraploid neurons of ϳ2% of all neurons was observed in AD. Our results indicate that at least two different mechanisms need to be distinguished giving rise to a tetraploid DNA content in the adult brain. Constitutional aneuploidy in differentiated neurons might be more frequent than previously thought. It is, however, not elevated in AD. In addition, in AD some neurons have re-entered the cell cycle and entirely passed through a functional interphase with a complete DNA replication.

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Section: Discussionmentioning

confidence: 99%

Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

Mosch

Morawski²,

Mittag³

et al. 2007

Journal of Neuroscience

239

248

View full text Add to dashboard Cite

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“…The number of injections was limited to between 3 and 7 in an attempt to avoid incorporation of 3H-TdR during repair of nuclear DNA. Larger amounts of circulating radioisotopes can produce damage to the DNA, whose repair, utilizing newly injected thymidine, could cause radioactivity of the nucleus without cell division (Kunzle, 1985;Rapp et al, 1985). However, the total of 16 injections to the 4 adult animals (Table 1) may be considered as equivalent to 16 independent labeling experiments (Rakic, 1985b).…”

Section: Electron Microscopy and Immunocytochemistrymentioning

confidence: 99%

Nature and fate of proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey

1988

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The nature of proliferative cells in the subgranular zone (SGZ) of the hippocampal region and the fate of their progeny was analyzed by 3H- thymidine (3H-TdR) autoradiography combined with immunocytochemistry at the light and electron microscopic levels in 18 rhesus monkeys ranging in age from late gestation to 17 years. Our analysis indicates that, during the last quarter of gestation and the first 3 postnatal months, the SGZ produces both glial and neuronal cells. These 2 major classes of cells originate from the 2 precursor lines and, following their mitotic division, migrate to the granular layer. During the juvenile period (4–6 months of age), neuronal production tapers off and most postmitotic cells remaining within the SGZ differentiate into glial elements. In postpubertal animals (3 years and older), the 3H-TdR- labeled cells in the dentate gyrus belong to several non-neuronal classes. The largest group was immunoreactive to the glial fibrillary acidic protein (GFAP) at both the light and electron microscopic levels, indicating their astrocytic nature. The remaining 3H-TdR- labeled, GFAP-negative cells had ultra-structural characteristics of either microglia, oligodendroglia, or their progenitory stem cells. Therefore, there is a continuing addition and/or turnover of the glial cells in the dentate gyrus of sexually mature monkeys, but, in contrast to the massive neurogenesis reported in adult rodents, the production of new neurons could not be detected after puberty. The significance of a stable population of neurons in the hippocampal formation of mature primates is discussed in relation to its possible function in memory.

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“…In addition, it has been recently shown that neurons are particularly sensitive to x-ray irradiation-induced DNA damage and apoptosis (Gobbel et al, 1998). Although the expression of several DNA repair proteins in the brain has been studied previously, our knowledge regarding the expression of the DNA mismatch repair proteins in neurons is limited (Kuenzle, 1985;Brooks et al, 1996;Corradi et al, 1996;Belloni et al, 1997;Marietta et al, 1998).…”

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confidence: 99%

Induction of Two DNA Mismatch Repair Proteins, MSH2 and MSH6, in Differentiated Human Neuroblastoma SH‐SY5Y Cells

Belloni

Uberti²,

Rizzini³

et al. 1999

Journal of Neurochemistry

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Abstract:The MutS homologues MSH2 and MSH6 form a heterodimeric protein complex that is involved in the recognition of base/base mismatches and insertion/deletion loops, as well as some other types of DNA damage. We investigated the expression of these proteins in undifferentiated and retinoic acid-differentiated human neuroblastoma SH-SY5Y cells by immunocytochemistry, western blot analysis, and RT-PCR. Nuclei from undifferentiated SH-SY5Y cells were found to be immunoreactive to anti-MSH2 and anti-MSH6 antibodies. Following differentiation, the cells stop dividing and change morphology to acquire a neuron-like phenotype. Under these conditions, both anti-MSH2 and anti-MSH6 immunoreactivities were still detectable, although the signals were somewhat less intense. When these cells were exposed for 2 h to neurotoxic concentrations of doxorubicin (50 nM ), they exhibited a marked and homogeneous increase of both anti-MSH2 and anti-MSH6 immunoreactivities. As revealed by western blot analysis, these effects were associated with increased protein content and were dose-dependent. Using RT-PCR technology, we also found that doxorubicin treatment did not change MSH2 or MSH6 mRNA levels. Our data indicate that human postmitotic, neuron-like cells constitutively express the molecular machinery devoted to recognition of DNA mismatches and that this system is activated by specific treatment leading to cell death. These findings might help clarify the molecular mechanisms underlying various human neurological diseases that are associated with deficiencies in DNA repair and/or a high rate of DNA damage acquisition. Key Words: DNA damage -DNA repair-Neurotoxicity-Differentiation-Neuroblastoma. J. Neurochem. 72, 974 -979 (1999).DNA repair is the cellular response to damage introduced into DNA either in the form of replication errors or as a result of reactions with a plethora of modifying agents, including free radicals. To overcome the deleterious effects of DNA damage, all organisms have evolved highly efficient repair systems. DNA mismatch repair is the process by which incorrectly paired nucleotides in DNA are recognized and repaired. Mismatches in DNA may arise as replication errors and as a result of base damage; in eukaryotic cells, they are recognized primarily by hMutS␣, a heterodimer of the MutS homologues MSH2 and MSH6 (Drummond et al

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Enzymology of DNA Replication and Repair in Brain

Cited by 3 publications

References 30 publications

Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

Aneuploidy and DNA Replication in the Normal Human Brain and Alzheimer's Disease

Nature and fate of proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey

Induction of Two DNA Mismatch Repair Proteins, MSH2 and MSH6, in Differentiated Human Neuroblastoma SH‐SY5Y Cells

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