8-Methoxypsoralen induced mutations are highly targeted at crosslinkable sites of photoaddition on the non-transcribed strand of a mammalian chromosomal gene.

Sage, Évelyne; Drobetsky, Elliot; Moustacchi, E.

doi:10.1002/j.1460-2075.1993.tb05671.x

Cited by 50 publications

(40 citation statements)

References 46 publications

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“…As more UVA radiation was applied the mutation frequency clearly increased suggesting an error-prone cellular processing of crosslinks. These findings are in agreement with the previous observations of psoralen adduct repair where the interstrand crosslink was found to be a highly mutagenic lesion (23,24). On the other hand, the 1.3% mutation frequency value proposes that only a minority of the 25% of the molecules shown to contain a crosslink became mutated.…”

Section: Discussionsupporting

confidence: 92%

Repair of triple helix directed psoralen adducts in human cells

Sandor¹,

Bredberg²

1994

Nucl Acids Res

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Triple helix forming oligonucleotides can direct DNA damaging agents at specific sites in an intact double helix. In our study, triple helix formation was demonstrated in a SV40 based shuttle vector treated with psoralen linked to a 22-mer purine rich oligonucleotide. UVA irradiation caused a covalent linkage of the oligonucleotide through the psoralen to the mutational supF marker gene of the plasmid. After passage in the Jurkat human cell line the recovered vector was analysed in an indicator bacterial strain and mutants were collected. The presence of adducts in the target sequence did not reduce the yield of replicated progeny vector molecules, indicating repair of triple helix associated monoadducts and cross-links. Mutations were highly targeted to a six nucleotide long region of the target sequence. The number of target sequence mutants obtained after triple helix directed psoralen treatment was approximately 160 times higher than with free psoralen. A further investigation of the exact mechanism of the mutational process could make triple helix directed mutagenesis a more useful tool in gene therapy, antiviral therapy, and in studies on DNA repair and genome organisation.

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Section: Discussionsupporting

confidence: 92%

Repair of triple helix directed psoralen adducts in human cells

Sandor¹,

Bredberg²

1994

Nucl Acids Res

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“…Several studies have shown that PUVA is a potent mutagen and a carcinogen (7)(8)(9)(10)(11)(12)(13). In vitro studies have revealed that PUVA induces mutations in mammalian cells predominantly at 5'-TA sequences, which are sites for formation of both monoadducts and interstrand DNA cross-links (7,8,13). Although it is known that PUVA-induced DNA cross-links and monoadducts play a direct role in mutagenesis, their role in tumorigenesis is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that the increased risk of developing skin cancer in PUVA-treated patients is quite complex and is dependent on patient's genetic background, the number and intensity of PUVA treatments, and prior exposure to other carcinogens. Nonetheless, although the mutagenic and carcinogenic effects of PUVA treatment have been well established (7)(8)(9)(10)(11)(12)(13), the molecular mechanisms by which PUVA induces skin cancer are obscure.…”

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confidence: 99%

Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers.

Nataraj

Black

Ananthaswamy

1996

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

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A combination of psoralen and ultraviolet A radiation (PUVA) is widely used in the treatment of psoriasis. However, PUVA treatment increases the risk of developing skin cancer in psoriasis patients and induces skin cancer in mice. Since the DNA damage induced by PUVA is quite different from that induced by UV, we investigated whether PUVA-induced mouse skin cancers display carcinogenspecific mutations in the p53 tumor suppressor gene. The results indicated that 10 of 13 (77%) PUVA-induced skin tumors contained missense mutations predominantly at exons 6 and 7. In contrast, tumor-adjacent, PUVA-exposed skin from tumor-bearing animals did not exhibit p53 mutation in exons 4-8. Interestingly, about 40% of all mutations in PUVA-induced skin tumors occurred at 5'-TA sites, and an equal number of mutations occurred at one base flanking 5'-TA or 5'-TAT sites. Since PUVA induces DNA cross-links exclusively at these sites and since UV "signature" mutations were rarely detected in PUVA-induced skin cancers, we can conclude that PUVA acts as a carcinogen by inducing unique PUVA signature mutations in p53. This finding may have implications for identifying the etiology of skin cancer in psoriasis patients who have undergone PUVA therapy.

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“…Relative contributions of MAs versus biadducts. Most mutations observed in studies of PUVA-induced mutagenesis in mammalian cells are substitutions at T ⅐ A base pairs (4,25,34,53; for a review, see reference 33). In the present study, PUVA treatment resulted in a substantial increase in T ⅐ A3C ⅐ G replication errors (Table 2).…”

Section: Discussionmentioning

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

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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...

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8-Methoxypsoralen induced mutations are highly targeted at crosslinkable sites of photoaddition on the non-transcribed strand of a mammalian chromosomal gene.

Cited by 50 publications

References 46 publications

Repair of triple helix directed psoralen adducts in human cells

Repair of triple helix directed psoralen adducts in human cells

Signature p53 mutation at DNA cross-linking sites in 8-methoxypsoralen and ultraviolet A (PUVA)-induced murine skin cancers.

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

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