Possible roles of <i>β</i>-elimination and <i>δ</i>-elimination reactions in the repair of DNA containing AP (apurinic/apyrimidinic) sites in mammalian cells

Bailly, Véronique; Verly, Walter G.

doi:10.1042/bj2530553

Cited by 85 publications

(79 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The tetrahydrofuran residue has a hydrogen in the place of a hydroxyl group at the 1' position of the natural AP site and is resistant to cleavage by 1-elimination. Several repair-related enzymes, such as AP lyase (formerly called class I AP endonuclease) and dRPase appear to be inactive at a tetrahydrofuran residue (1,6). It is likely that one of these enzymes is essential for DNA polymerase 3-dependent repair.…”

Section: Discussionmentioning

confidence: 99%

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Matsumoto¹,

Kim²,

Bogenhagen³

1994

Mol. Cell. Biol.

265

192

View full text Add to dashboard Cite

DNA damage frequently leads to the production of apurinic/apyrimidinic (AP) sites, which are presumed to be repaired through the base excision pathway. For detailed analyses of this repair mechanism, a synthetic analog of an AP site, 3-hydroxy-2-hydroxymethyltetrahydrofuran (tetrahydrofuran), has been employed in a model system. Tetrahydrofuran residues are efficiently repaired in a Xenopus laevis oocyte extract in which most repair events involve ATP-dependent incorporation of no more than four nucleotides (Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 9:3750-3757, 1989; Y. Matsumoto and D. F. Bogenhagen, Mol. Cell. Biol. 11:44414447, 1991). Using a series of column chromatography procedures to fractionate X. laevis ovarian extracts, we developed a reconstituted system of tetrahydrofuran repair with five fractions, three of which were purified to near homogeneity: proliferating cell nuclear antigen (PCNA), AP endonuclease, and DNA polymerase 8. This PCNA-dependent system repaired natural AP sites as well as tetrahydrofuran residues. DNA polymerase ,I was able to replace DNA polymerase b only for repair of natural AP sites in a reaction that did not require PCNA. DNA polymerase a did not support repair of either type of AP site. This result indicates that AP sites can be repaired by two distinct pathways, the PCNA-dependent pathway and the DNA polymerase ,8-dependent pathway.Base excision repair is a major pathway for repair of damaged bases in DNA (8). In this pathway, a DNA-Nglycosylase initiates repair by removing a specifically modified base, leaving an apurinic/apyrimidinic (AP) site. AP sites are also generated by spontaneous or induced base loss. Since AP sites arise so frequently, it is reasonable to expect that cells should have evolved very efficient mechanisms to repair this sort of damage.To study the mechanism of repair of AP sites, we have taken advantage of the ability to insert a single copy of a synthetic analog of an AP site, 3-hydroxy-2-hydroxymethyltetrahydrofuran (tetrahydrofuran), at a specific position in a covalently closed circular DNA (cccDNA) (17,23,29 (215) 728-4333. ever, several lines of evidence suggested that DNA polymerase ,B might not be the only polymerase involved in repair of AP sites. First, our early experiments showed that repair of the tetrahydrofuran residue was inhibited by aphidicolin, as expected if repair involves a high-molecular-weight DNA polymerase (unpublished data). Second, biochemical analyses of yeast mutants indicated that DNA polymerase E is responsible for this reaction (33). While a discrepancy concerning the identity of the repair polymerase may be the result of intrinsic differences in the experimental systems, some uncertainties could be eliminated if a reconstituted system which catalyzes the repair reaction with purified factors were available. In this paper, we present results obtained by fractionating the X. laevis ovarian extract, leading to development of a reconstituted system. This system consists of five fractions, including proli...

show abstract

Section: Discussionmentioning

confidence: 99%

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Matsumoto¹,

Kim²,

Bogenhagen³

1994

Mol. Cell. Biol.

265

192

View full text Add to dashboard Cite

show abstract

“…The lysine-rich N-terminal tails of the histones extend from the protein core, making various contacts with the DNA minor groove. The proximity of nucleosomal AP sites to these basic residues is expected to accelerate cleavage of the lesion relative to naked DNA (26)(27)(28). Previously, Povirk showed that the oxidized abasic lesion produced by bleomycin undergoes rapid strand scission when produced in chromatin (27).…”

mentioning

confidence: 99%

Rapid DNA–protein cross-linking and strand scission by an abasic site in a nucleosome core particle

Sczepanski

Wong

McKnight

et al. 2010

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

175

316

View full text Add to dashboard Cite

Apurinic/apyrimidinic (AP) sites are ubiquitous DNA lesions that are highly mutagenic and cytotoxic if not repaired. In addition, clusters of two or more abasic lesions within one to two turns of DNA, a hallmark of ionizing radiation, are repaired much less efficiently and thus present greater mutagenic potential. Abasic sites are chemically labile, but naked DNA containing them undergoes strand scission slowly with a half-life on the order of weeks. We find that independently generated AP sites within nucleosome core particles are highly destabilized, with strand scission occurring ∼60-fold more rapidly than in naked DNA. The majority of core particles containing single AP lesions accumulate DNA-protein cross-links, which persist following strand scission. The N-terminal region of histone protein H4 contributes significantly to DNA-protein crosslinks and strand scission when AP sites are produced approximately 1.5 helical turns from the nucleosome dyad, which is a known hot spot for nucleosomal DNA damage. Reaction rates for AP sites at two positions within this region differ by ∼4-fold. However, the strand scission of the slowest reacting AP site is accelerated when it is part of a repair resistant bistranded lesion composed of two AP sites, resulting in rapid formation of double strand breaks in high yields. Multiple lysine residues within a single H4 protein catalyze double strand cleavage through a mechanism believed to involve a templating effect. These results show that AP sites within the nucleosome produce significant amounts of DNA-protein cross-links and generate double strand breaks, the most deleterious form of DNA damage.chromatin | oxidative damage | histone modification E xogenously and endogenously produced agents continuously damage DNA. More than 70 types of damage have been identified, and significant effort is expended to determine which of these lesions are biologically important (1, 2). The apurinic/apyrimidinic (AP) site is a ubiquitous form of DNA damage that is produced in excess of 10,000 lesions per cell each day (3). This highly mutagenic lesion results from spontaneous hydrolysis of native and damaged nucleotides. AP sites are also formed as intermediates during base excision repair of alkylated and oxidized nucleotides and are themselves removed by multiple enzymatic pathways (4, 5). In mammalian cells incision of the AP's 5′-phosphate by Ape1, followed by excision of the resulting 5′-terminal 2′-deoxyribose phosphate by DNA polymerase β is the major pathway for removing the lesion. Redundant repair pathways are reflective of the high mutagenic potential and large quantities of AP produced and are indicative of their physiological significance. Mammalian cells lacking Ape1, the major base excision repair protein responsible for incising AP sites, are embryonic lethal (6). Recent observations reinforce the perception that AP sites are cytotoxic. For instance, formation of bursts of AP sites by the natural product leinamycin is postulated to be the source of this antitumor agent's cy...

show abstract

“…The effect of polyamines on apurinic/apyrimidinic (AP) DNA has been investigated previously by several investigators [25,20], and the cleavage induced is most probably caused by B-elimination [25,31]. We have compared the efficiency of three different polyamines which share a common structure.…”

Section: Discussionmentioning

confidence: 99%

Action of spermidine, N¹‐acetylspermidine, and N⁸acetylspermidine at apurinic sites in DNA

1990

View full text Add to dashboard Cite

The cleavage efficiency of spermidine and its acetyl derivatives (Ni-acetylspennidine and Ns-acetylspermidine) at apurinic sites in DNA were examined by PAGE-urea analysis. The three polyamines induced different rates of cleavage when compared at 1 mM concentrations. The order of effectiveness were: spermidine > p-acetylspennidine > Wacetylspermidine. Thus a decrease in efficiency was observed when the first order aminogroups of spermidine were blocked. The N-%mino-group of spermidine was less effective in inducing cleavage at AP-sites than the Ni'-amino-group.Among several proposed models of polyamine-DNA interactions, our results can best be explained by the model postulated by Liquori et al.[6].

show abstract

Possible roles of β-elimination and δ-elimination reactions in the repair of DNA containing AP (apurinic/apyrimidinic) sites in mammalian cells

Cited by 85 publications

References 32 publications

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Rapid DNA–protein cross-linking and strand scission by an abasic site in a nucleosome core particle

Action of spermidine, N¹‐acetylspermidine, and N⁸acetylspermidine at apurinic sites in DNA

Contact Info

Product

Resources

About

Possible roles of β-elimination and δ-elimination reactions in the repair of DNA containing AP (apurinic/apyrimidinic) sites in mammalian cells

Cited by 85 publications

References 32 publications

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Proliferating cell nuclear antigen-dependent abasic site repair in Xenopus laevis oocytes: an alternative pathway of base excision DNA repair.

Rapid DNA–protein cross-linking and strand scission by an abasic site in a nucleosome core particle

Action of spermidine, N1‐acetylspermidine, and N8acetylspermidine at apurinic sites in DNA

Contact Info

Product

Resources

About

Action of spermidine, N¹‐acetylspermidine, and N⁸acetylspermidine at apurinic sites in DNA