Terminally Differentiated Human Neurons Repair Transcribed Genes but Display Attenuated Global DNA Repair and Modulation of Repair Gene Expression

Nouspikel, Thierry; Hanawalt, Philip C.

doi:10.1128/mcb.20.5.1562-1570.2000

Cited by 180 publications

(146 citation statements)

References 32 publications

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“…These results suggest that in neuronal cells, replication compartment formation is impaired, and HSV-1 is unable to cause a DNA damage response. This finding is consistent with reports that neurons are inefficient at DNA repair (38,39) and that ATM is specifically down-regulated when neuronal precursors are differentiated to a neuronal lineage (40). The cellular transcription factor Oct-1 is required for efficient assembly of HSV-1 replication compartments (41).…”

Section: Viral Replication and Growth Are Greater In The Presence Of supporting

confidence: 81%

DNA repair proteins affect the lifecycle of herpes simplex virus 1

Lilley

Carson²,

Muotri³

et al. 2005

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

224

344

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We report that herpes simplex virus 1 (HSV-1) infection can activate and exploit a cellular DNA damage response that aids viral replication in nonneuronal cells. Early in HSV-1 infection, several members of the cellular DNA damage-sensing machinery are activated and accumulate at sites of viral DNA replication. When this cellular response is abrogated, formation of HSV-1 replication centers is retarded, and viral production is compromised. In neurons, HSV-1 replication centers fail to mature, and the DNA damage response is not initiated. These data suggest that the failure of neurons to mount a DNA damage response to HSV-1 may contribute to the establishment of latency.replication ͉ Mre11 ͉ damage ͉ signaling ͉ ataxia telangiectasia mutated

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Section: Viral Replication and Growth Are Greater In The Presence Of supporting

confidence: 81%

DNA repair proteins affect the lifecycle of herpes simplex virus 1

Lilley

Carson²,

Muotri³

et al. 2005

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

224

344

View full text Add to dashboard Cite

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“…1). In particular the GGR subpathway is greatly attenuated in human neurons, either primary (1) or derived from NT2 neuroteratoma cells (2), whereas TCR is still active in both cases. In the terminally differentiated cells, however, the nontranscribed strand in active genes is also efficiently repaired, a phenomenon that we have termed differentiation-associated repair (DAR) and which we have reasoned is required to maintain lesion-free templates for TCR.…”

mentioning

confidence: 99%

Impaired nucleotide excision repair upon macrophage differentiation is corrected by E1 ubiquitin-activating enzyme

Nouspikel

Hanawalt

2006

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

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Global nucleotide excision repair is greatly attenuated in terminally differentiated mammalian cells. We observed this phenomenon in human neurons and in macrophages, noting that the transcriptioncoupled repair pathway remains functional and that there is no significant reduction in levels of excision repair enzymes. We have discovered that ubiquitin-activating enzyme E1 complements the repair deficiency in macrophage extracts, and although there is no reduction in the concentration of E1 upon differentiation, our results indicate a reduction in phosphorylation of E1. In preliminary studies, we have identified the basal transcription factor TFIIH as the potential target for ubiquitination. We suggest that this unusual type of regulation at the level of the E1 enzyme is likely to affect numerous cellular processes and may represent a strategy to coordinate multiple phenotypic changes upon differentiation by using E1 as a ''master switch.'' DNA repair ͉ TFIIH ͉ ubiquitination ͉ monocytes ͉ differentiated N ucleotide excision repair (NER) is the most versatile DNA repair system; it handles a wide variety of lesions, from UV-induced pyrimidine dimers to bulky chemical adducts, to intrastrand DNA cross-links and even bound protein fragments. The early steps in NER can be divided into two subpathways: global genomic repair (GGR) that recognizes and removes lesions throughout the genome, and transcription-coupled repair (TCR) that preferentially repairs the transcribed strand of active genes, most likely by using translocating RNA polymerase as a lesion sensor.The efficiency of NER is known to be affected by cellular differentiation (reviewed in ref. 1). In particular the GGR subpathway is greatly attenuated in human neurons, either primary (1) or derived from NT2 neuroteratoma cells (2), whereas TCR is still active in both cases. In the terminally differentiated cells, however, the nontranscribed strand in active genes is also efficiently repaired, a phenomenon that we have termed differentiation-associated repair (DAR) and which we have reasoned is required to maintain lesion-free templates for TCR.It seems likely that attenuation of NER at the global genome level, and its reliance on TCR and DAR to maintain the essential active genes, is common in terminally differentiated cells. Indeed, studies with other differentiated cell systems have yielded similar results. Among numerous examples, rat skeletal myocytes exhibited a decrease in repair synthesis in the course of differentiation (3, 4), whereas TCR was less affected (4). Mouse 3T3 cells displayed attenuated UV-induced repair synthesis after differentiation into adipocytes (5). The repair of UV-induced lesions was reduced in differentiated keratinocytes, compared with that in cells from the basal layers of human skin (6). Human neuroblastomas repaired benzo[a]pyrene diol-epoxide adducts less rapidly after differentiation (7), and differentiated mouse neuroblastomas exhibited similar deficiencies in the repair of UV-induced lesions (8).What is the mechanism by whic...

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“…This effectively results in rodent cells being able to survive much larger amounts of some DNA-damaging agents than other mammal cells, human cells included; the latter attempt to repair all genomic lesions regardless of their location in actively transcribed or untranscribed genomic regions. The same mechanism has been found to operate in human cells that are in a permanent G0-arrest, such as the differentiated neurons and quiescent circulating B-lymphocytes [100][101][102]. It is not known whether this applies to rodent ESC also, especially considering that the chromatin of mammal stem cells is in hyperplastic state [103]; so it is more accessible to the repair machinery than in differentiated cells anyway.…”

Section: Signalling Mediated By Erk1/2mentioning

confidence: 99%