Defective poly(adenosine diphosphoribose) synthesis in Xeroderma pigmentosum

Berger, Nathan A.; Sikorski, Georgina W.; Petzold, Shirley J.; Kurohara, Kevin K.

doi:10.1021/bi00543a006

Cited by 137 publications

(36 citation statements)

References 15 publications

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“…Complementation group A is one of the most severe forms of this genetic disease (39). There are reports that XP cells are defective in the synthesis of poly(ADPribose) in response to UV irradiation (40,41). In contrast to HL 60 cells, the internucleosomal DNA fragmentation (Fig.…”

Section: Resultsmentioning

confidence: 99%

Poly(ADP-ribosyl)ation of Histone H1 Correlates with Internucleosomal DNA Fragmentation during Apoptosis

Yoon

Kim

Kang

et al. 1996

Journal of Biological Chemistry

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The biochemical role of poly(ADP-ribosyl)ation on internucleosomal DNA fragmentation associated with apoptosis was investigated in HL 60 human premyelocytic leukemia cells. It was found that UV light and chemotherapeutic drugs including adriamycin, mitomycin C, and cisplatin increased poly(ADP-ribosyl)ation of nuclear proteins, particularly histone H1. A poly(ADP-ribose) polymerase inhibitor, 3-aminobenzamide, prevented both internucleosomal DNA fragmentation and histone H1 poly(ADP-ribosyl)ation in cells treated with the apoptosis inducers. When nuclear chromatin was made accessible to the exogenous nuclease in a permeabilized cell system, chromatin of UV-treated cells was more susceptible to micrococcal nuclease than the chromatin of control cells. Suppression of histone H1 poly-(ADP-ribosyl)ation by 3-aminobenzamide reduced the micrococcal nuclease digestibility of internucleosomal chromatin in UV-treated cells. These results suggest that the poly(ADP-ribosyl)ation of histone H1 correlates with the internucleosomal DNA fragmentation during apoptosis mediated by DNA damaging agents. This suggestion is supported by the finding that xeroderma pigmentosum cells which are defective in introducing incision at the site of DNA damage, failed to induce DNA fragmentation as well as histone H1 poly(ADP-ribosyl)ation after UV irradiation. We propose that poly(ADPribosyl)ation of histone H1 protein in the early stage of apoptosis facilitates internucleosomal DNA fragmentation by increasing the susceptibility of chromatin to cellular endonuclease.Apoptosis is an active form of cellular suicide, a process that typically involves morphological changes such as the condensation of chromatin into clumps, nuclear fragmentation, and packaging of nuclear fragments into membrane-enclosed apoptotic bodies. These morphological changes are usually accompanied by biochemical changes including elevation of cytoplasmic Ca 2ϩ and internucleosomal DNA fragmentation (1). Many of the chemotherapeutic drugs and radiation which cause DNA damage are known to induce apoptosis (2-5). It is well established that a variety of DNA damaging agents lower the cellular NAD ϩ content by raising the specific activity of poly(ADPribose) polymerase (PARP) 1 (EC 2.4.2.30) that results from the conformational changes which occur when the zinc finger domains of the enzyme bind to the DNA strand breaks (6, 7). PARP is a nuclear enzyme which transfers the ADP-ribose moiety of NAD ϩ to nuclear proteins including PARP itself and histones in cells (8). In vitro studies have also revealed that topoisomerase I (9), RNA polymerase II (10), DNA polymerase ␣ (11), DNA polymerase ␤ (12), and terminal deoxynucleotidyl transferase (13) are the substrates of PARP. Thus, poly(ADPribosyl)ation has been implicated in many biological responses including DNA replication (14), DNA excision repair (15), cell differentiation (16), and tumor promotion (17).In recent years, the role of poly(ADP-ribosyl)ation in the cell death process has been discussed. The decrease in cellular PARP ...

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Section: Resultsmentioning

confidence: 99%

Poly(ADP-ribosyl)ation of Histone H1 Correlates with Internucleosomal DNA Fragmentation during Apoptosis

Yoon

Kim

Kang

et al. 1996

Journal of Biological Chemistry

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“…In fact, Jump et aL (10) found that ADP-ribosylation mainly occurred in regions of chromatin undergoing DNA synthesis. Finally, several authors observed a great increase of poly(ADP-ribose) polymerase activity upon the induction of DNA repair (35)(36)(37). It is tempting to suggest that this massive poly(ADP-ribosyl)ation would produce a relaxation phenomenon that would render the damaged DNA more accessible to repair enzymes.…”

Section: Discussionmentioning

confidence: 99%

Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure.

Poirier¹,

Murcia²,

Jongstra‐Bilen³

et al. 1982

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

443

291

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When rat pancreatic polynucleosomes were poly(ADP-ribosyl)ated with purified calfthymus poly(ADP-ribose) polymerase and examined by electron microscopy, a relaxation of their native zigzag structure was observed. At high ionic strengths control nucleosomes condensed into 250-A-thick fibers, but poly(ADP-ribosyl)ated polynucleosomes did not; they showed a close resemblance to chromatin depleted of histone HI. The relaxed state of poly(ADP-ribosyl)ated polynucleosomes was also confirmed by sedimentation velocity analysis. Histone HI was found to be the major histone acceptor of poly(ADP-ribose). Poly(ADP-ribose) linked to histone HI did not seem to cause its dissociation from the chromatin, but it impaired significantly its effect on chromatin condensation.Post-translational modifications of histones-e.g., phosphorylation (1), acetylation (2, 3), and poly(ADP-ribosyl)ation (4,5) have been suggested as possible mechanisms to modulate the nucleosomal structure during DNA transcription and replication.Poly(ADP-ribose) polymerase was suggested to be preferentially located at internucleosomal regions of HeLa cell nucleosomes (6, 7); its specific activity was shown to be highest at selected folded regions of 8-10 nucleosomes in higher-ordered chromatin (8). In addition, the poly(ADP-ribosyl)ation of several chromatin components, including all the histones, was demonstrated (9, 10). All these findings reinforced the suggestions of involvement of poly(ADP-ribosyl)ation in DNA replication, DNA repair, and gene expression through alteration of the chromatin structure.In order to test this hypothesis, pancreatic polynucleosomes (20-40 nucleosomes) were poly(ADP-ribosyl)ated by using purified calf thymus poly(ADP-ribose) polymerase. Changes of nucleosome structure were examined by electron microscopy and by ultracentrifugation and the poly(ADP-ribosyl)ated histones were characterized.MATERIALS AND METHODS Preparation ofPolynucleosomes. Rat pancreatic polynucleosomes were isolated as described (11). Nuclei were digested with micrococcal nuclease (Sigma) at 30°C for 2 min, with 0.5 unit of nuclease per mg of DNA. The polynucleosomes (20-40 nucleosomes) were isolated on linear 5-29% sucrose gradients by centrifugation at 260,000 X g for 150 min in a Beckman SW 41 rotor and were characterized by electron microscopy and circular dichroism.Poly(ADP-ribosyl)ation of Polynucleosomes. Polynucleosomes were poly(ADP-ribosyl)ated by using purified calf thymus poly(ADP-ribose) polymerase at 25°C in an incubation medium of 500 utl containing 8 jig of DNA-independent enzyme (12,13) Electron Microscopy. Chromatin samples diluted to 0.5 ,g/ ml (expressed as DNA concentration) with a buffer containing 5 mM triethanolamine at pH 7.4, 0.2 mM EDTA, and the appropriate concentration of NaCl (see figure legends) were fixed in 0.1% glutaraldehyde (Balzers, Lichtenstein) for 1 hr at room temperature. Adsorption of the specimens onto positively charged carbon-coated grids (400 mesh) was performed as described (14). The specimens were stained w...

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“…Despite the large difference in poly(ADP-ribosyl)ation, transformation is suppressed after exposure to each kind of agent (Tables 1 and 2), suggesting that transformation frequency is not directly dependent on the total amount and duration of poly(ADP-ribosyl)ation but more likely is dependent on specific proteins that are ADP-ribosylated. Fibroblasts from patients with many disorders that lead to abnormal carcinogen sensitivities or a high propensity for cancer, such as xeroderma pigmentosum (29), Cockayne syndrome (30), and Fanconi anemia (31), also exhibit abnormalities in the poly-(ADP-ribose) synthesis pathway. A causal relationship between ADP-ribosylation activity and y-glutamyl transpeptidase, an early marker of neoplasia, has also been reported (32).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

Borek¹,

Morgan²,

Ong³

et al. 1984

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

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Malignant transformation in vitro of hamster embryo cells and mouse C3H lOT'/2 cells by x-rays, ultraviolet light, and chemical carcinogens was inhibited by benzamide and by 3-aminobenzamide at concentrations that are specific for inhibition of poly(ADP-ribose) formation. These compounds slow the ligation stage of repair of x-ray and alkylation damage but not of ultraviolet light damage. At high concentrations they also inhibited de novo synthesis of DNA purines and DNA methylation by S-adenosylmethionine. The suppression of transformation by the benzamides is in striking contrast to their reported effectiveness in enhancing sister chromatid exchange, mutagenesis, and killing in cells exposed to alkylating agents. Our results suggest that mechanisms regulating malignant transformation are different from those regulating DNA repair, sister chromatid exchange, and mutagenesis and may be associated with changes in gene regulation and expression caused by alterations in poly(ADP-ribosyl)ation.Malignant transformation of cells in vitro by radiation or chemical carcinogens is a reproducible quantitative system for studying the mechanisms of carcinogenesis (1-7). Although fixation of transformation and mutagenesis involves DNA metabolism and cell replication (2, 4-6), the numbers and kinds of genes involved are not known. Poly(ADP-ribose) is an important cellular regulatory molecule (8, 9) and its synthesis can be inhibited by 3-aminobenzamide (3ABzA) and benzamide (BzA). We therefore investigated the effects of these inhibitors on transformation by a variety of DNAdamaging agents with careful comparison to their effects on DNA repair and nucleotide precursor pathways over a range of concentrations. These agents, at concentrations below those at which side effects were evident, inhibited malignant transformation in vitro, in contrast to their reported enhancement of sister chromatid exchange (10-12) and mutagenesis (13) Mouse embryo fibroblast cells C3H 10T1/2 (clone 8), originally obtained from C. Heidelberger (University of Southern California, Los Angeles), were treated as described (3,7). Stock cultures were maintained at 370C, aerated with 5% CO2 in air, in Eagle's basal medium containing 10% heatinactivated fetal calf serum, penicillin (50 units/ml), and streptomycin (50 tkg/ml).At 24 hr after plating, cells were irradiated with a Siemens 300-kVp constant-potential generator with an additional filter of 0.2 mm of Cu at room temperature with 3 or 4 Gy of xrays at a dose rate of 0.322 Gy/min and incubated at 37°C in 5% C02/95% air with weekly changes of medium. After a 10-day incubation period for the hamster cells (1, 2) and 6 weeks for the lOT1/2 cells (2, 3, 7), cultures were fixed and stained with Giemsa stain. Assays for cell survival, cloning efficiency, and transformation were carried out as described previously for the hamster cells (1-4) and for the C3H 10T1/2 cells (2, 3, 7). For experiments with UV light, C3H 10T1/2 cells were exposed to 10-13 J/m2 (254 nm, dose rate of 0.15-1.3 J/m2_sec).For ex...

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Defective poly(adenosine diphosphoribose) synthesis in Xeroderma pigmentosum

Cited by 137 publications

References 15 publications

Poly(ADP-ribosyl)ation of Histone H1 Correlates with Internucleosomal DNA Fragmentation during Apoptosis

Poly(ADP-ribosyl)ation of Histone H1 Correlates with Internucleosomal DNA Fragmentation during Apoptosis

Poly(ADP-ribosyl)ation of polynucleosomes causes relaxation of chromatin structure.

Inhibition of malignant transformation in vitro by inhibitors of poly(ADP-ribose) synthesis.

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