New insights in DNA repair: preferential repair of transcriptionally active DNA

Terleth, Carrol; P, van de Putte; Brouwer, Jaap

doi:10.1093/mutage/6.2.103

Cited by 49 publications

(12 citation statements)

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“…5B). The 25-fold difference between human and mouse primary skin cells has been documented by others and may reflect a fundamental difference in the extent to which these respective mammalian species deal with UV damage, presumably at the level of the noncoding genomic repair of pyrimidine dimers and 6-4 photoproducts [35,36].…”

Section: Resultsmentioning

confidence: 65%

Elevated DNA Excision Repair Capacity in the Extraembryonic Mesoderm of the Midgestation Mouse Embryo

Latimer

Hultner

Cleaver

et al. 1996

Experimental Cell Research

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In order to determine whether there is differential cell-type-specific DNA repair we measured the nucleotide excision repair capacity of the four distinct cell lineages that comprise the extraembryonic yolk sac using the unscheduled DNA synthesis assay. Yolk sacs from mouse embryos at 11.5-12.5 days gestation were microdissected to yield purified trophoblast, parietal endoderm, mesoderm, and visceral endoderm, as well as fetal skin fibroblasts which were then grown as primary explants. At this midgestational stage of development, the yolk sac provides essential functions for the sustenance of the embryo while the complex process of organogenesis is proceeding in the liver, kidney, and gut. Trophoblast giant cells, parietal endoderm, and visceral endoderm all demonstrated low levels of unscheduled DNA synthesis consistent with levels measured in adult mouse skin fibroblasts. As has previously been documented, embryonic mouse skin fibroblasts were reproducibly 2-to 3-fold higher than adult mouse skin fibroblasts in levels of DNA excision repair. The extraembryonic mesoderm, however, displayed a statistically significant level of unscheduled DNA synthesis 10-fold higher than adult mouse skin fibroblasts or the other lineages of the midgestation yolk sac. Further, the S-indexes of these lineages were also determined to assess the possible relevance of differential repair to the proliferative status of the cells. These data demonstrate that DNA excision repair capacity is lineage-specific during embryogenesis in the mouse. These studies may begin to provide a context for understanding the perplexing developmental aspects such as the characteristic congenital abnormalities associated with the human heritable DNA repair deficiency diseases.

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Section: Resultsmentioning

confidence: 65%

Elevated DNA Excision Repair Capacity in the Extraembryonic Mesoderm of the Midgestation Mouse Embryo

Latimer

Hultner

Cleaver

et al. 1996

Experimental Cell Research

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“…Damage produced by UV light and certain chemical carcinogens is repaired more rapidly in transcriptionally active DNA compared to the genome as a whole (1,2) due to a faster repair of damage in the transcribed strand (3,4). Strandspecific repair of UV damage occurs in Escherichia coli (5,6) and Saccharomyces cerevisiae (7)(8)(9) as well as mammalian cells and hence appears to be a highly conserved pathway.…”

mentioning

confidence: 99%

Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome.

Leadon

Cooper²

1993

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

197

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Cells from patients with Cockayne syndrome (CS), which are sensitive to killing by UV although overall damage removal appears normal, are specifically defective in repair of UV damage in actively transcribed genes. Because several CS strains display cross-sensitivity to killing by ionizing radiation, we examined whether ionizing radiation-induced damage in active genes is preferentially repaired by normal cells and whether the radiosensitivity of CS cells can be explained by a defect in this process. We found that ionizing radiation-induced damage was repaired more rapidly in the transcriptionally active metallothionein IIA (MTIIA) gene than in the inactive MTIIB gene or in the genome overall in normal cells as a result of faster repair on the transcribed strand of MTIIA. Cells of the radiosensitive CS strain CS1AN are completely defective in this strand-selective repair of ionizing radiation-induced damage, although their overall repair rate appears normal. CS3BE cells, which are intermediate in radiosensitivity, do exhibit more rapid repair of the transcribed strand but at a reduced rate compared to normal cells. Xeroderma pigmentosum complementation group A cells, which are hypersensitive to UV light because of a defect in the nucleotide excision repair pathway but do not show increased sensitivity to ionizing radiation, preferentially repair ionizing radiation-induced damage on the transcribed strand of MTIIA. Thus, the ability to rapidly repair ionizing radiation-induced damage in actively transcribing genes correlates with cell survival. Our results extend the generality of preferential repair in active genes to include damage other than bulky lesions.

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“…Preferential Repair Requires RNA Pol H Transcription. The association of strand bias in repair with transcription has been well documented for mammalian and bacterial cells (2,3). For example, the RNA pol II inhibitor a-amanitin has been shown to inhibit the strand bias in repair of transcribed -genes in rodent (19) and human cells (20,21).…”

Section: Resultsmentioning

confidence: 99%

Preferential repair of cyclobutane pyrimidine dimers in the transcribed strand of a gene in yeast chromosomes and plasmids is dependent on transcription.

Sweder

Hanawalt

1992

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

162

112

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While preferential repair of the transcribed strands within active genes has been demonstrated in organisms as diverse as humans and Escherichia colt, it has not previously been shown to occur in chromosomal genes in the yeast Saccharomyces cerevisiae. We found that repair of cyclobutane pyrimidine dimers in the transcribed strand of the expressed RPB2 gene in the chromosome of a repair-proficient strain is much more rapid than that in the nontranscribed strand. Furthermore, a copy of the RPB2 gene borne on a centromeric ARSI plasmid showed the same strand bias in repair. To investigate the relation of this strand bias to transcription, we studied repair in a yeast strain with the temperature-sensitive mutation, rpbl-1, in the largest subunit of RNA polymerase II. When exponentially growing rpbl-1 cells are shifted to the nonpermissive temperature, they rapidly cease mRNA synthesis. At the permissive temperature, both rpbl-1 and the wild-type, parental cells exhibited rapid, proficient repair in the transcribed strand of chromosomal and plasmid-borne copies of the RPB2 gene. At the nonpermissive temperature, the rate of repair in the transcribed strand in rpbl-1 cells was reduced to that in the nontranscribed strand.These findings establish the dependence of strand bias in repair on transcription by RNA polymerase II in the chromosomes and in plasmids, and they validate the use of plasmids for analysis of the relation of repair to transcription in yeast.Both eukaryotes and prokaryotes carry out excision repair of DNA damage after exposure to UV light (1). The two major classes of lesions produced are 5-5, 6-6 cis-syn cyclobutane pyrimidine dimers (CPDs) and pyrimidine-pyrimidone (6-4) photoproducts, both of which are removed from the DNA. Furthermore, CPD removal has been shown in mammalian cells to be faster in transcriptionally active genes when compared to the genome overall (for recent reviews, see refs. 2 and 3) and more rapid in the transcribed strand in expressed genes than in the nontranscribed strand (4). This preferential repair of the transcribed strand in expressed genes has also been shown for the lac genes in the Escherichia coli chromosome (5) and for the uvrC gene in vitro (6). Thus, it seems likely that preferential DNA repair of active genes is a conserved pathway for nucleotide excision repair in both prokaryotes and eukaryotes. However, preferential DNA repair of the transcribed strand of an active chromosomal gene has not yet been shown in the unicellular eukaryote Saccharomyces cerevisiae.Recent reports of transcription-associated nucleotide excision repair in yeast are seemingly inconsistent. Studies of repair in unique chromosomal DNA sequences did not show a strand bias in repair (7-9). In contrast, Smerdon and Thoma and colleague (10,11) reported that excision repair of CPDs in a plasmid was rapid for transcribed strands, while nontranscribed sequences were slowly repaired. To resolve these differences we have compared the repair rates in the same expressed sequence in a plasmid...

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New insights in DNA repair: preferential repair of transcriptionally active DNA

Cited by 49 publications

References 0 publications

Elevated DNA Excision Repair Capacity in the Extraembryonic Mesoderm of the Midgestation Mouse Embryo

Elevated DNA Excision Repair Capacity in the Extraembryonic Mesoderm of the Midgestation Mouse Embryo

Preferential repair of ionizing radiation-induced damage in the transcribed strand of an active human gene is defective in Cockayne syndrome.

Preferential repair of cyclobutane pyrimidine dimers in the transcribed strand of a gene in yeast chromosomes and plasmids is dependent on transcription.

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