Differential repair of DNA damage in the human metallothionein gene family.

Leadon, Steven A.; Snowden, Mildred

doi:10.1128/mcb.8.12.5331

Cited by 71 publications

(33 citation statements)

References 30 publications

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“…Several studies have shown that pyrimidine dimers are repaired more rapidly in actively transcribed genes than in inactive genes (16,17,23). The association between transcription and repair at the gene level is further supported by the findings that repair enzymes are selectively directed to the template strand of the DNA in organisms as diverse as yeasts, bacteria, and mammals (20,21,29) and by the isolation of a transcriptionrepair coupling factor from Escherichia coli cells (27).…”

Section: Methodsmentioning

confidence: 62%

DNA repair defects associated with chromosomal translocation breaksite regions.

Beecham¹,

Jones²,

Link³

et al. 1994

Mol. Cell. Biol.

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Using an assay that measures the removal of UV-induced pyrimidine dimers in specific DNA sequences, we have found that the Pvt-1, immunoglobulin H-Ca (IgH-Ca), and IgL-K loci are poorly repaired in normal B lymphoblasts from plasmacytoma-susceptible BALB/cAnPt mice. Breaksites in these genes are associated with the chromosomal translocations that are found in >95% of BALB/cAnPt plasmacytomas. In contrast to those from BALB/cAnPt mice, B lymphoblasts from plasmacytoma-resistant DBA12N mice rapidly repair Pvt-1, There is considerable evidence that chromosomal translocations play a direct role in the development of many leukemias and lymphomas. It is generally believed that these abnormal recombinations contribute to neoplastic transformation by altering the structure, function, and/or expression of proto-oncogenes or antioncogenes. Chromosomal translocations that deregulate the c-myc proto-oncogene are nearly universally present in two B-lymphocytic tumors: spontaneous human Burkitt's lymphoma and pristane-induced mouse plasmacytomas. In both cases, the chromosome bearing the c-myclPvt-1 gene complex is broken and reciprocally translocated to one of the three chromosomes that carry immunoglobulin (Ig) genes.The molecular mechanisms responsible for the formation of nonrandom chromosomal translocations are not known.Molecular analysis of the translocation breaksites in a number of mouse plasmacytomas has shown that each breaksite is unique. Thus, the mutational process is not site specific. However, the distribution of breaksites is not random.

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Section: Methodsmentioning

confidence: 62%

DNA repair defects associated with chromosomal translocation breaksite regions.

Beecham¹,

Jones²,

Link³

et al. 1994

Mol. Cell. Biol.

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“…For a number of mammalian genes, the limits of the DNase I sensitivity domain have been shown to coincide with the location of matrix attachment regions to define a topologically sequestered functional unit (20,29,35). That domain size may also play a role in DNA repair is suggested by results presented by several groups investigating repair in the Chinese hamster DHFR gene (5), the Chinese hamster (28) and human (19) metallothionein gene family, and the human P-actin gene (14). In all cases, it was found that the efficiently repaired region was considerably larger than the gene of interest.…”

Section: Resultsmentioning

confidence: 74%

Xeroderma pigmentosum complementation group C cells remove pyrimidine dimers selectively from the transcribed strand of active genes.

Venema¹,

Hoffen²,

Karcagi³

et al. 1991

Mol. Cell. Biol.

307

166

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We have measured the removal of UV-induced pyrimidine dimers from DNA fragments of the adenosine deaminase (ADA) and dihydrofolate reductase (DHFR) genes in primary normal human and xeroderma pigmentosum complementation group C (XP-C) cells. Using strand-specific probes, we show that in normal cells, preferential repair of the 5' part of the ADA gene is due to the rapid and efficient repair of the transcribed strand. Within 8 h after irradiation with UV at 10 J m-2, 70% of the pyrimidine dimers in this strand are removed. The nontranscribed strand is repaired at a much slower rate, with 30% dimers removed after 8 h. Repair of the transcribed strand in XP-C cells occurs at a rate indistinguishable from that in normal cells, but the nontranscribed strand is not repaired significantly in these cells. Similar results were obtained for the DHFR gene. In the 3' part of the ADA gene, however, both normal and XP-C cells perform fast and efficient repair of either strand, which is likely to be caused by the presence of transcription units on both strands. The factor defective in XP-C cells is apparently involved in the processing of DNA damage in inactive parts of the genome, including nontranscribed strands of active genes. These findings have important implications for the understanding of the mechanism of UV-induced excision repair and mutagenesis in mammalian cells.

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“…This high level of hMTIIA basal constitutive expression coupled with the gene's remarkable inducibility makes hMTIIA easily assayable and, therefore, provides an ideal model for studying transcriptional regulation in eukaryotic cells. Although there are reports that hMTIIA may be regulated by gene amplification (47), DNA methylation (33), or posttranscriptional events (60), there is no question that the principal mechanism of regulation lies at the level of transcriptional initiation (44).…”

mentioning

confidence: 99%

trans Repression of the Human Metallothionein IIA Gene Promoter by PZ120, a Novel 120-Kilodalton Zinc Finger Protein

Tang

Westling

Seto

1999

Molecular and Cellular Biology

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Metallothioneins are small, highly conserved, cysteine-rich proteins that bind a variety of metal ions. They are found in virtually all eukaryotic organisms and are regulated primarily at the transcriptional level. In humans, the predominant metallothionein gene is hMTIIA, which accounts for 50% of all metallothioneins expressed in cultured human cells. The hMTIIA promoter is quite complex. In addition to cis-acting DNA sequences that serve as binding sites for trans-acting factors such as Sp1, AP1, AP2, AP4, and the glucocorticoid receptor, the hMTIIA promoter contains eight consensus metal response element sequences. We report here the cloning of a novel zinc finger protein with a molecular mass of 120 kDa (PZ120) that interacts specifically with the hMTIIA transcription initiation site. The PZ120 protein is ubiquitously expressed in most tissues and possesses a conserved poxvirus and zinc finger (POZ) motif previously found in several zinc finger transcription factors. Intriguingly, we found that a region of PZ120 outside of the zinc finger domain can bind specifically to the hMTIIA DNA. Using transient-transfection analysis, we found that PZ120 repressed transcription of the hMTIIA promoter. These results suggest that the hMTIIA gene is regulated by an additional negative regulator that has not been previously described.Metallothioneins (MTs) were initially discovered by biochemists searching for tissue constituents responsible for the natural accumulation of cadmium. They have been reported to occur throughout the animal kingdom, as well as in plants, eukaryotic microorganisms, and prokaryotes (reviewed in references 25 and 35). In humans, MTs have been isolated from the liver (57), cultured cells (41, 59), and the brain (growth inhibitory factor) (75). They are present in four distinguishable forms known as hMTI, hMTII, hMTIII, and hMTIV (reviewed in references 2, 25, 37, and 55).Different tissues and cell types synthesize different MTs in various levels. However, the hMTIIA gene is responsible for the majority of MTs expressed in most tissues in humans (41). This high level of hMTIIA basal constitutive expression coupled with the gene's remarkable inducibility makes hMTIIA easily assayable and, therefore, provides an ideal model for studying transcriptional regulation in eukaryotic cells. Although there are reports that hMTIIA may be regulated by gene amplification (47), DNA methylation (33), or posttranscriptional events (60), there is no question that the principal mechanism of regulation lies at the level of transcriptional initiation (44).The interest in transcriptional regulation of the hMTIIA gene centers on three key issues. First, shortly after the cloning of the hMTIIA gene, there was an explosive increase of interest in the identification of the cis-acting DNA sequences in the hMTIIA promoter that are responsible for basal and induced transcription. Second, many laboratories have intensely pursued the identification of trans-acting proteins that interact with these cis-acting DNA sequences. Fina...

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Differential repair of DNA damage in the human metallothionein gene family.

Cited by 71 publications

References 30 publications

DNA repair defects associated with chromosomal translocation breaksite regions.

DNA repair defects associated with chromosomal translocation breaksite regions.

Xeroderma pigmentosum complementation group C cells remove pyrimidine dimers selectively from the transcribed strand of active genes.

trans Repression of the Human Metallothionein IIA Gene Promoter by PZ120, a Novel 120-Kilodalton Zinc Finger Protein

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