The Poly-ADP-Ribosylation System of Higher Eukaryotes: How Can It Do What?

Althaus, Felix R.; Collinge, Margaret A.; Loetscher, Pius; Mathis, Georg A.; Naegeli, Hanspeter; Panzeter, Phyllis L.; Realini, Claudio

doi:10.1007/978-3-642-75682-5_3

Cited by 6 publications

(6 citation statements)

References 20 publications

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“…In agreement with our data showing that ADPRT is not a critical regulatory component in the DNA repair process are studies demonstrating that DNA repair was apparently independent of ADPRT (Satoh and Lindahl 1992;Satoh et al 1993;Smulson et al 1994). These results suggest that ADPRT acts as a "nick-protection" molecule to prevent accidental homologous recombination events and is needed for the maintenance of chromatin structure (Althaus et al 1990;Satoh et al 1994).…”

Section: Dna Repair Processes Are Not Affected By the Lack Of Poly(adsupporting

confidence: 92%

Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

Wang¹,

Auer²,

Stingl³

et al. 1995

Genes Dev.

740

504

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Poly(ADP-ribosyl)ation is catalyzed by NAD + :protein(ADP-ribosyl)transferase (ADPRT), a chromatinassociated enzyme which, in the presence of DNA breaks, transfers ADP-ribose from NAD + to nuclear proteins. This post-translational modification has been implicated in many fundamental processes, like DNA repair, chromatin stability, cell proliferation, and cell death. To elucidate the biological function of ADPRT and poly(ADP-ribosyl)ation in vivo the gene was inactivated in the mouse germ line. Mice homozygous for the ADPRT mutation are healthy and fertile. Analysis of mutant tissues and fibroblasts isolated from mutant fetuses revealed the absence of ADPRT enzymatic activity and poly(ADP-ribose), implying that no poly(ADP-ribosyl)ated proteins are present. Mutant embryonic fibroblasts were able to efficiently repair DNA damaged by UV and alkylating agents. However, proliferation of mutant primary fibroblasts as well as thymocytes following y-radiation in vivo was impaired. Moreover, mutant mice are susceptible to the spontaneous development of skin disease as -30% of older mice develop epidermal hyperplasia. The generation of viable ADPRT-/-mice negates an essential role for this enzyme in normal chromatin function, but the impaired proliferation and the onset of skin lesions in older mice suggest a function for ADPRT in response to environmental stress.

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Section: Dna Repair Processes Are Not Affected By the Lack Of Poly(adsupporting

confidence: 92%

Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

Wang¹,

Auer²,

Stingl³

et al. 1995

Genes Dev.

740

504

View full text Add to dashboard Cite

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“…The resulting binding is strong enough to resist high salt concentrations, strong acids, detergents, and chaotropes (). Moreover, the affinity between H1 and ADP-ribose polymers is high enough to compete for H1−DNA interactions ( , ). Other chromatin proteins have also been shown to interact noncovalently with ADP-ribose polymers and it is noteworthy that most of these proteins, such as, e.g., p53, which plays an important role in carcinogenesis, can also be covalently ADP-ribosylated ( − ).…”

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confidence: 99%

In Vitro Induction of H1−H1 Histone Cross-Linking by Adenosine Diphosphate−Ribose Polymers

et al. 2000

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It is well-known that H1-H1 interactions are very important for the induction of 30 nm chromatin fiber and that, among all posttranslational modifications, poly(ADP-ribosyl)ation is one of those capable of modifying chromatin structure, mainly through H1 histone. As this protein can undergo both covalent and noncovalent modifications by poly(ADP-ribosyl)ation, our aim was to investigate whether and how ADP-ribose polymers, by themselves, are able to affect the formation of H1-H1 oligomers, which are normally present in a condensed chromatin structure. The results obtained in our in vitro experimental system indicate that ADP-ribose polymers are involved in chromatin decondensation. This conclusion was reached as the result of two different observations: (a) H1 histone molecules can be hosted in clusters on ADP-ribose polymers, as shown by their ability to be chemically cross-linked, and (b) H1 histone has a higher affinity for ADP-ribose polymers than for DNA; ADP-ribose polymers compete, in fact, with DNA for H1 histone binding.

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“…Histones are also a physiological target of ADP-ribose modifications in carcinogen-treated mammalian cells in vivo (20,21). Thus, the reversible modification of DNA-protein interactions (14,15,22,23) by protein ADP-ribosylation may be the underlying molecular mechanism for the transient formation of free DNA domains in eukaryotic excision repair.…”

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confidence: 99%

Uncoupling of DNA excision repair and nucleosomal unfolding in poly (ADP-ribose)-depleted mammalian cells

Mathis

Althaus

1990

Carcinogenesis

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The repair of DNA damage in eukaryotic cells is closely coupled with local changes of chromatin structure such that newly synthesized repair patches transiently appear in 'free' DNA domains with increased accessibility to enzymatic and chemical probes. We have isolated these domains from mammalian cells repairing bulky DNA adducts. During the first 3 h of repair, excision of adducts occurred exclusively in free DNA and was closely linked with the appearance of newly synthesized repair patches. Following depletion of chromatin-bound poly(ADP-ribose), the repositioning of repair patches into these domains was completely blocked, although overall repair patch synthesis was unaltered. Concomitantly, DNA adducts were no longer excised and tended to accumulate in free DNA domains. Our results suggest a tight coupling of the excision step with the formation of free DNA domains by a mechanism involving poly ADPrnbosylation of chromatin proteins.In chromatin of mammalian cells, newly synthesized DNA repair patches exhibit a transient micrococcal nuclease hypersensitivity. This hypersensitivity is thought to reflect local disruptions in the tightly packed nucleosomal organization of chromatin, causing exposure of 'free' DNA domains (for review see 1,2). The function of these domains as well as the mechanisms involved in their formation are unknown. We have speculated that the post-translational poly ADP-ribosylation of chromatin proteins might be involved in the formation of free DNA domains in DNA excision repair. Poly ADP-ribosylation is catalyzed by the enzyme poly(ADP-ribose)polymerase (1,3,4; EC 2.4.2.30). Following activation by DNA nicks, this enzyme operates in a strictly processive manner (5). Continuous treatment of living cells with benzamide, a competitive inhibitor of this enzyme (3,4,6), results in the degradation of chromatin-bound ADP-ribose polymers (7) by the enzyme poly(ADP-ribose)glycohydrolase (3,4). Using non-replicating adult rat hepatocytes in primary monolayer culture, we have established conditions for the complete depletion of chromatin-associated poly(ADP-ribose) (7,8). Hepatocytes survive up to 9 days under these conditions and maintain expression of liver-specific functions (8). Thus, poly(ADPribose)-depleted hepatocytes represent a convenient model system to study the role of poly ADP-ribosylation in specific steps of DNA repair.We have previously shown that unfolded free DNA domains can be isolated from the chromatin of intact mammalian cells by taking advantage of their preferential accessibility to 8-methoxypsoralen (9). Upon intercalation into free DNA domains of living cells, 8-methoxypsoralen can be photoactivated to form bifunctional DNA adducts crosslinking the two DNA strands. Crosslinked (free) DNA domains can then be isolated quantitatively following a denaturation/renaturation treatment and subsequent nuclease SI digestion of non-crosslinked DNA strands (for details see 9).Here we have isolated free DNA domains from non-replicating hepatocytes (9

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The Poly-ADP-Ribosylation System of Higher Eukaryotes: How Can It Do What?

Cited by 6 publications

References 20 publications

Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

Mice lacking ADPRT and poly(ADP-ribosyl)ation develop normally but are susceptible to skin disease.

In Vitro Induction of H1−H1 Histone Cross-Linking by Adenosine Diphosphate−Ribose Polymers

Uncoupling of DNA excision repair and nucleosomal unfolding in poly (ADP-ribose)-depleted mammalian cells

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