Mutagenic Effects of Psoralen-Induced Photoadducts and their Repair in Eukaryotic Cells

Averbeck, D.; Dardalhon, M.; Magaña‐Schwencke, Nieve

doi:10.1007/978-1-4615-3732-8_103

Cited by 7 publications

(6 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…RPA binds to triplexes with high affinity, with or without XPA, whereas XPA binds only in conjunction with RPA, but contributes to specificity by selectively diminishing nonspecific binding and͞or aggregation of RPA to undamaged DNA. Psoralen monoadducts and crosslinks are, at least in part, recognized and repaired by NER in human cells (39)(40)(41)(42)(43)(44)(45)(46). Psoralen monoadducts are somewhat helix-stabilizing, whereas crosslinks are helix-destabilizing (47,48).…”

Section: Discussionmentioning

confidence: 99%

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Vásquez

Christensen

et al. 2002

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

111

128

View full text Add to dashboard Cite

Nucleotide excision repair (NER) plays a central role in maintaining genomic integrity by detecting and repairing a wide variety of DNA lesions. Xeroderma pigmentosum complementation group A protein (XPA) is an essential component of the repair machinery, and it is thought to be involved in the initial step as a DNA damage recognition and͞or confirmation factor. Human replication protein A (RPA) and XPA have been reported to interact to form a DNA damage recognition complex with greater specificity for damaged DNA than XPA alone. The mechanism by which these two proteins recognize such a wide array of structures resulting from different types of DNA damage is not known. One possibility is that they recognize a common feature of the lesions, such as distortions of the helical backbone. We have tested this idea by determining whether human XPA and RPA proteins can recognize the helical distortions induced by a DNA triple helix, a noncanonical DNA structure that has been shown to induce DNA repair, mutagenesis, and recombination. We measured binding of XPA and RPA, together or separately, to substrates containing triplexes with three, two, or no strands covalently linked by psoralen conjugation and photoaddition. We found that RPA alone recognizes all covalent triplex structures, but also forms multivalent nonspecific DNA aggregates at higher concentrations. XPA by itself does not recognize the substrates, but it binds them in the presence of RPA. Addition of XPA decreases the nonspecific DNA aggregate formation. These results support the hypothesis that the NER machinery is targeted to helical distortions and demonstrate that RPA can recognize damaged DNA even without XPA.triple helix ͉ nucleotide excision repair B ecause genome stability is critical for cell survival, extremely sensitive DNA repair mechanisms have evolved to protect the genome from both internal and external assaults. Defects in these repair mechanisms can lead to severe disorders such as xeroderma pigmentosum, ataxia telangiectasia, Fanconi anemia, and Bloom syndrome (reviewed in refs. 1-5). One of the major consequences of these defects is an enhanced predisposition to cancer. It has been reported that 80-90% of human cancers are the result of DNA damage (6).Many types of DNA damage, spontaneous and induced, develop from both endogenous and exogenous sources. Exogenous damages, both chemical and physical, arise from exposure to UV and ionizing radiation and from natural and synthetic chemicals. Cellular metabolic processes lead to internal sources of DNA damage; for example, it is estimated that loss of a purine base (depurination) occurs at a rate of nearly 20,000 events per cell per day (7).In humans, different types of DNA damage are thought to be repaired by one of several mechanisms, including nucleotide excision repair (NER; reviewed in refs. 8 and 9). NER removes covalent DNA lesions and is the only known mechanism for removing bulky DNA adducts in humans. The damaged base is removed by endonucleolytic cleavage of the phosphodiester bond...

show abstract

Section: Discussionmentioning

confidence: 99%

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Vásquez

Christensen

et al. 2002

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

111

128

View full text Add to dashboard Cite

show abstract

“…As far as cosmetic preparations are concerned a new assay system using human suction blister fluid after application of furcoumarins to measure the concentration and the genotoxic (mutagenic) activity of photoreactive compounds including complex mixtures appears to be particularly useful (Averbeck et al, 1989b). Not only the amount of genotoxic substances which pass into the skin (Morliere et al, 1989), but also the bioavailability and the part of the compounds which is photomutagenic can be accurately determined by physico-chemical methods (HPLC etc.).…”

Section: Furocoumarins Of Photochemotherapeutic Interestmentioning

confidence: 99%

Recent Advances in Psoralen Phototoxicity Mechanism

Averbeck

1989

Photochem & Photobiology

219

114

View full text Add to dashboard Cite

“…These chemicals present the unique aspect of possessing two reactive groups, allowing monoaddition to one DNA strand, similarly to many genotoxic agents, or biaddition to both strands, creating ICs (33,44). Numerous studies with tissue cultures and animals have underscored the genotoxic consequences of PUVA treatment, which include mutagenesis, clastogenesis, and carcinogenesis (1,3,12,35). Despite such well-established genotoxicity, psoralens of natural origin are widespread components of vegetarian diets at potentially genotoxic levels (13), and synthetic derivatives are becoming increasingly important as photochemotherapeutic agents (for a review, see reference 24).…”

mentioning

confidence: 99%

Strand Specificity of Mutagenic Bypass Replication of DNA Containing Psoralen Monoadducts in a Human Cell Extract

Thomas

Svoboda

Vos

et al. 1996

Molecular and Cellular Biology

View full text Add to dashboard Cite

Psoralens are mutagenic compounds of vegetable origin that are used as photosensitizing agents in the treatment of various skin diseases, blood cell cancer, and autoimmune disorders. To study the mechanism of mutagenicity of psoralens in humans, we examined the efficiency and fidelity of simian virus 40 origindependent replication in a human cell extract of M13mp2 DNA randomly treated with the psoralen derivative 4-hydroxymethyl-4,5,8-trimethyl psoralen plus UVA irradiation. Replication of DNA treated with variable amounts of 4-hydroxymethyl-4,5,8-trimethyl psoralen and a fixed UVA fluence was inhibited in a concentration-dependent manner. However, covalently closed monomer-length circular replication products were observed. Product analysis by renaturing agarose gel electrophoresis after cross-linking with 250-to 280-nm UV light indicated that approximately 1 of 9 psoralen monoadducts was bypassed during in vitro replication. Introduction of product DNA into Escherichia coli to score replication errors in the lacZ␣ reporter gene demonstrated that replication of the damaged DNA was more mutagenic than was replication of undamaged DNA. Sequence analysis of lacZ mutants revealed that damage-dependent replication errors were predominantly T ⅐ A3C ⅐ G transitions, transversions at C ⅐ G base pairs, and deletions of single A ⅐ T base pairs, the last occurring most frequently in homopolymeric runs. A comparison of error specificities with two substrates having the replication origin asymmetrically placed on opposite sides of the mutational target suggests that the lagging-strand replication apparatus is less accurate than the leading-strand replication apparatus for psoralen monoadduct-dependent deletion errors. A model is proposed based on the preferential loopout of the monoadducted base from the strand that templates retrograde discontinuous synthesis.DNA replication in eukaryotic cells is a complex process requiring a variety of proteins to synthesize the leading and lagging strands in an asymmetric yet coordinated manner (14). Because of this asymmetry, DNA adducts that escape repair may have different potentials for blocking replication or promoting replication infidelity, depending on which strand the adduct is located on. For example, in mammalian cells deficient in excision repair, mutations were predominantly found on one of the two strands of the hprt gene (6,19,20,50,51), leading to the suggestion that the fidelity of translesion bypass is more error prone on the leading strand (20, 51).To study the processes that determine the fidelity of DNA replication, we have been using the SV40 replication system as a model for human chromosomal replication (for reviews, see references 29 and 37). Using substrates containing the SV40 origin of replication, we (27,30,31,41) and others (11) have shown that the replication apparatus in mammalian cell extracts is quite accurate when replicating undamaged DNA, with an error rate ranging from less than or equal to 6.2 ϫ 10 Ϫ6 to 1 ϫ 10 Ϫ7 error per nucleotide. These observ...

show abstract

Mutagenic Effects of Psoralen-Induced Photoadducts and their Repair in Eukaryotic Cells

Cited by 7 publications

References 80 publications

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Human XPA and RPA DNA repair proteins participate in specific recognition of triplex-induced helical distortions

Recent Advances in Psoralen Phototoxicity Mechanism

Strand Specificity of Mutagenic Bypass Replication of DNA Containing Psoralen Monoadducts in a Human Cell Extract

Contact Info

Product

Resources

About