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Alain Sarasin - One of the best experts on this subject based on the ideXlab platform.
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CPDs and 6-4PPs play different roles in UV-induced cell death in normal and NER-deficient human cells.
DNA Repair, 2008Co-Authors: Keronninn Moreno De Lima-bessa, Melissa Gava Armelini, Vanessa Chiganças, Gustavo P. Amarante-mendes, Jacqueline F. Jacysyn, Alain Sarasin, Carlos Frederico Martins MenckAbstract:Ultraviolet (UV) light generates two major DNA lesions: cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6-4)-Pyrimidone photoproducts (6-4PPs), but the specific participation of these two lesions in the deleterious effects of UV is a longstanding question. In order to discriminate the precise role of unrepaired CPDs and 6-4PPs in UV-induced responses triggering cell death, human fibroblasts were transduced by recombinant adenoviruses carrying the CPD-photolyase or 6-4PP-photolyase cDNAs. Both photolyases were able to prevent UV-induced apoptosis in cells deficient for nucleotide excision repair (NER) to a similar extent, while in NER-proficient cells UV-induced apoptosis was prevented only by CPD-photolyase, with no effects observed when 6-4PPs were removed by the specific photolyase. These results strongly suggest that both CPDs and 6-4PPs contribute to UV-induced apoptosis in NER-deficient cells, while in NER-proficient cells, CPDs are the only lesions responsible for UV-killing, probably due to the rapid repair of 6-4PPs by NER. As a consequence, the difference in skin photosensitivity, including carcinogenesis, of most of the xeroderma pigmentosum patients and of normal people is probably not only a quantitative aspect, but depends on the type of DNA damage induced by sunlight and its rate of repair.
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CPDs and 6-4PPs play different roles in UV-induced cell death in normal and NER-deficient human cells
DNA Repair, 2008Co-Authors: Keronninn Moreno De Lima-bessa, Melissa Gava Armelini, Vanessa Chiganças, Gustavo P. Amarante-mendes, Jacqueline F. Jacysyn, Alain Sarasin, Carlos Frederico Martins MenckAbstract:Ultraviolet (UV) light generates two major DNA lesions: cyclobutane pyrimidine dimers (CPDs) and pyrimidine-(6-4)-Pyrimidone photoproducts (6-4PPs), but the specific participation of these two lesions in the deleterious effects of UV is a longstanding question. In order to discriminate the precise role of unrepaired CPDs and 6-4PPs in UV-induced responses triggering cell death, human fibroblasts were transduced by recombinant adenoviruses carrying the CPD-photolyase or 6-4PP-photolyase cDNAs. Both photolyases were able to prevent UV-induced apoptosis in cells deficient for nucleotide excision repair (NER) to a similar extent, while in NER-proficient cells UV-induced apoptosis was prevented only by CPD-photolyase, with no effects observed when 6-4PPs were removed by the specific photolyase. These results strongly suggest that both CPDs and 6-4PPs contribute to UV-induced apoptosis in NER-deficient cells, while in NER-proficient cells, CPDs are the only lesions responsible for UV-killing, probably due to the rapid repair of 6-4PPs by NER. As a consequence, the difference in skin photosensitivity, including carcinogenesis, of most of the xeroderma pigmentosum patients and of normal people is probably not only a quantitative aspect, but depends on the type of DNA damage induced by sunlight and its rate of repair. © 2007 Elsevier B.V. All rights reserved.
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mutagenicity of a unique thymine thymine dimer or thymine thymine pyrimidine Pyrimidone 6 4 photoproduct in mammalian cells
Nucleic Acids Research, 1996Co-Authors: Annabelle Gentil, Le F Page, A Margot, Angela Borden, Christopher W. Lawrence, Alain SarasinAbstract:The mutagenic properties of UV-induced photoproducts, both the cis-syn thymine-thymine dimer (TT) and the thymine-thymine pyrimidine Pyrimidone (6-4) photoproduct [T(6-4)T] were studied in mammalian cells using shuttle vectors. A shuttle vector able to replicate in both mammalian cells and bacteria was produced in its single-stranded DNA form. A unique photoproduct was inserted at a single restriction site and after recircularization of the single-stranded DNA vector, this latter was transfected into simian COS7 cells. After DNA replication the vector was extracted from cells and used to transform bacteria. Amplified DNA was finally analyzed without any selective screening, DNA from randomly picked bacterial colonies being directly sequenced. Our results show clearly that both lesions are mutagenic, but at different levels. Mutation frequencies of 2 and 60% respectively were observed with the TT dimer and the T(6-4)T. With the TT dimer the mutations were targeted on the 3'-T. With the T(6-4)T a large variety of mutations were observed. A majority of G-->T transversions were semi-targeted to the base before the 5'-T of the photoproduct. These kinds of mutations were not observed when the same plasmid was transfected directly into SOS-induced JM105 bacteria or when the T(6-4)T oligonucleotide inserted in a different plasmid was replicated in SOS-induced SMH10 Escherichia coil bacteria. These semi-targeted mutations are therefore the specific result of bypass of the T(6-4)T lesion in COS7 cells by one of the eukaryotic DNA polymerases.
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specific uv induced mutation spectrum in the p53 gene of skin tumors from dna repair deficient xeroderma pigmentosum patients
Proceedings of the National Academy of Sciences of the United States of America, 1993Co-Authors: Nicolas Dumaz, Alain Sarasin, Christiane Drougard, Leela DayagrosjeanAbstract:Abstract The UV component of sunlight is the major carcinogen involved in the etiology of skin cancers. We have studied the rare, hereditary syndrome xeroderma pigmentosum (XP), which is characterized by a very high incidence of cutaneous tumors on exposed skin at an early age, probably due to a deficiency in excision repair of UV-induced lesions. It is interesting to determine the UV mutation spectrum in XP skin tumors in order to correlate the absence of repair of specific DNA lesions and the initiation of skin tumors. The p53 gene is frequently mutated in human cancers and represents a good target for studying mutation spectra since there are > 100 potential sites for phenotypic mutations. Using reverse transcription-PCR and single-strand conformation polymorphism to analyze > 40 XP skin tumors (mainly basal and squamous cell carcinomas), we have found that 40% (17 out of 43) contained at least one point mutation on the p53 gene. All the mutations were located at dipyrimidine sites, essentially at CC sequences, which are hot spots for UV-induced DNA lesions. Sixty-one percent of these mutations were tandem CC-->TT mutations considered to be unique to UV-induced lesions; these mutations are not observed in internal human tumors. All the mutations, except two, must be due to translesion synthesis of unrepaired dipyrimidine lesions left on the nontranscribed strand. These results show the existence of preferential repair of UV lesions [either pyrimidine dimers or pyrimidine-Pyrimidone (6-4) photoproducts] on the transcribed strand in human tissues.
Pascale Clivio - One of the best experts on this subject based on the ideXlab platform.
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ab initio study of the 5r and 5s tt pyrimidine h5 6 4 Pyrimidone photoproducts implications on the design of new biologically relevant analogues
Journal of Organic Chemistry, 2002Co-Authors: Francoisyves Dupradeau, Dominique Guillaume, Pascal Sonnet, Hans Martin Senn, Pascale ClivioAbstract:A computational study of a series of N 1 - and/or C 6 -alkyl-5,6-dihydrothymine diastereomers at theory levels up to MP4(SDTQ)/6-31G*//HF/6-31G* and MP2/6-311G**//HF/6-31G* has demonstrated the respective importance of the substituents at positions 1, 5, and 6 on the energetically favored conformation of each isomer. Results obtained both in the gas and condensed phase indicate that unsubstitution of the N 1 -position favors a half-chair conformation with the C 5 -and C 6 -substituents in the equatorial position. On the other hand, in the case of the (6S)-1,6-dimethyl-5,6-dihydrothymine, the C 6 -substituent adopts the axial position to minimize its van der Waals interactions with the N 1 -substituent. Furthermore, if the configuration at the C 5 -dihydrothymine position has no resultant influence on the total molecular free energy, when a Pyrimidone substituent is introduced at the dihydrothymine C 6 -position, additional repulsive forces between the C 5 - and C 6 -substituents make the diaxially substituted half-chair conformation the most energetically favorable one. These results indicate that the observed C 6 -axially substituted conformation of the thymine-thymine pyrimidine h 5 (6-4) Pyrimidone photoproducts is not necessarily induced by the macrocyclic structure. They also nicely explain the formation mechanism of these photoproduct derivatives, and allow the prediction of the conformation of new analogues.
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further insight in the photochemistry of dna structure of a 2 imidazolone 5 4 Pyrimidone adduct derived from the mutagenic pyrimidine 6 4 Pyrimidone photolesion by uv irradiation
Journal of the American Chemical Society, 2002Co-Authors: Martial Thomas, Jeanlouis Fourrey, Dominique Guillaume, Pascale ClivioAbstract:Pyrimidine (6−4) Pyrimidone photoproducts represent one of the major mutagenic and carcinogenic class of DNA damage produced by UV exposure. At present, besides their conversion to their Dewar valence isomer, (6−4) photoproducts are generally believed to be photostable, and the observed biological properties of Paterno−Buchi-derived photoproducts are, thus far, exclusively attributed to these two types of compounds. Using a model system (2) relevant to DNA photochemistry, we have observed that the 5‘-base moiety of the (6−4) thymine dimer 3, under far-UV radiation, is able to undergo a ring contraction leading to a 2-oxoimidazoline, 1. This unprecedented secondary photochemical reaction constitutes the first report of a major photomodification affecting (6−4) photoproducts and strongly questions the biological stability of the (6−4) adducts under UV light with 2-imidazolone (5−4) Pyrimidone adducts being possibly another source of endogenous DNA damage.
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diastereoselective synthesis of 5 r and 5 s tt pyrimidine h5 6 4 Pyrimidone photoproducts structural analogues of the mutagenic uv induced tt 6 4 photolesion
Chemical Communications, 2001Co-Authors: Sandra Karina Angulo Matus, Leticia Quintero, Jeanlouis Fourrey, Pascale ClivioAbstract:Two pyrimidine (6-4) Pyrimidone photoproduct derivatives, highly valuable to probe the substituent influence during polymerase replicative bypass, were prepared; one (1a) by diastereoselective Raney nickel reductive desulfurization of the s5(6-4) adduct of TpT (3) and the other (1b) by alkaline treatment of 1a.
Thierry Douki - One of the best experts on this subject based on the ideXlab platform.
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pyrimidine 6 4 Pyrimidone photoproducts in uva irradiated dna photosensitization or photoisomerization
ChemPhotoChem, 2020Co-Authors: Thierry DoukiAbstract:Formation of pyrimidine dimers in DNA is a major initiating event in the induction of skin cancer. Model experiments suggest that, upon absorption of UVA, one type of dimers induced by UVB, the pyrimidine (6‐4) Pyrimidone photoproducts, photosensitizes the formation of mutagenic cyclobutane pyrimidine dimers by triplet ‐triplet energy transfer (TTET). We investigated whether this photoreaction actually took place when 64PP were located within a DNA duplex rather than added as external sensitizers like in available data. Our results show that this process is not detectable in DNA and double‐stranded oligonucleotides exposed to a combination of UVB and UVA. TTET could only be observed, as a very minor photoreaction, in a short single‐stranded oligonucleotide bearing a 64PP. It may be concluded that 64PP‐mediated TTET does not significantly contribute to UV‐induced DNA damage. In contrast, the photoisomerization of 64PP into their Dewar valence isomers is very efficient.
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Pyrimidine (6‐4) Pyrimidone photoproducts in UVA‐irradiated DNA: photosensitization or photoisomerization?
ChemPhotoChem, 2019Co-Authors: Thierry DoukiAbstract:Formation of pyrimidine dimers in DNA is a major initiating event in the induction of skin cancer. Model experiments suggest that, upon absorption of UVA, one type of dimers induced by UVB, the pyrimidine (6‐4) Pyrimidone photoproducts, photosensitizes the formation of mutagenic cyclobutane pyrimidine dimers by triplet ‐triplet energy transfer (TTET). We investigated whether this photoreaction actually took place when 64PP were located within a DNA duplex rather than added as external sensitizers like in available data. Our results show that this process is not detectable in DNA and double‐stranded oligonucleotides exposed to a combination of UVB and UVA. TTET could only be observed, as a very minor photoreaction, in a short single‐stranded oligonucleotide bearing a 64PP. It may be concluded that 64PP‐mediated TTET does not significantly contribute to UV‐induced DNA damage. In contrast, the photoisomerization of 64PP into their Dewar valence isomers is very efficient.
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Formation of UV-induced DNA damage contributing to skin cancer development
Photochemical and Photobiological Sciences, 2018Co-Authors: Jean Cadet, Thierry DoukiAbstract:UV-induced DNA damage plays a key role in the initiation phase of skin cancer. Their yield and chemical structure strongly depend on the wavelength.UV-induced DNA damage plays a key role in the initiation phase of skin cancer. When left unrepaired or when damaged cells are not eliminated by apoptosis, DNA lesions express their mutagneic properties, leading to the activation of proto–oncogene or the inactivation of tumor suppression genes. The chemical nature and the amount of DNA damage strongly depend on the wavelength of the incident photons. The most energetic part of the solar spectrum at the Earth's surface (UVB, 280–320 nm) leads to the formation of cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6–4) Pyrimidone photoproducts (64PPs). Less energetic but 20–times more intense UVA (320–400 nm) also induces the formation of CPDs together with a wide variety of oxidatively generated lesions such as single strand breaks and oxidized bases. Among those, 8–oxo–7,8–dihydroguanine (8–oxoGua) is the most frequent since it can be produced by several mechanisms. Data available on the respective yield of DNA photoproducts in cells and skin show that exposure to sunlight mostly induces pyrimidine dimers, which explains the mutational signature found in skin tumors, with lower amounts of 8–oxoGua and strand breaks. The present review aims at describing the basic photochemistry of DNA and discussing the quantitative formation of the different UV–induced DNA lesions reported in the literature. Additional information on mutagenesis, repair and photoprotection is briefly provided.
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dna photochemistry geometrically unconstrained pyrimidine 6 4 Pyrimidone photoproducts do photoisomerize
Organic Letters, 2015Co-Authors: Thierry Douki, Silvestre Rebelomoreira, Nadege Hamon, Pierrealain BayleAbstract:Structural features are of major importance for the formation of mutagenic photoproducts in DNA. It was recently reported that lack of constraints between two adjacent nucleosidic units prevents the conversion of pyrimidine (6–4) Pyrimidone photoproducts into their Dewar valence isomers. We here report that this is not the case for the thymidine photoproducts which, although unconstrained, are quantitatively converted into photolysis products identified as Dewar valence isomers by mass spectrometry and NMR and infrared spectroscopies.
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Solar uv radiation-induced dna bipyrimidine photoproducts: Formation and mechanistic insights
Topics in Current Chemistry, 2015Co-Authors: Jean Cadet, Andre Grand, Thierry DoukiAbstract:© Springer-Verlag Berlin Heidelberg 2014. This review chapter presents a critical survey of the main available information on the UVB and UVA bipyrimidine photoproducts which constitute the predominant recipient classes of photo-induced DNA damage. Evidence is provided that UVB irradiation of isolated DNA in aqueous solutions and in cells gives rise to the predominant generation of cis-syn cyclobutane pyrimidine dimers (CPDs) and, to a lesser extent, of pyrimidine (6-4) Pyrimidone photoproducts (6-4PPs), the importance of which is strongly primary sequence dependent. A notable change in the photoproduct distribution is observed when DNA either in the dry or in desiccated microorganisms is exposed to UVC or UVB photons with an overwhelming formation of 5-(α-thymidyl)-5,6-dihydrothymidine, also called spore photoproduct (dSP), at the expense of CPDs and 6-4PPs. UVA irradiation of isolated and cellular DNA gives rise predominantly to bipyrimidine photoproducts with the overwhelming formation of thymine-containing cyclobutane pyrimidine dimers at the exclusion of 6-4PPs. UVA photons have been shown to modulate the distribution of UVB dimeric pyrimidine photoproducts by triggering isomerization of the 6-4PPs into related Dewar valence isomers. Mechanistic aspects of the formation of bipyrimidine photoproducts are discussed in the light of recent photophysical and theoretical studies.
Christopher W. Lawrence - One of the best experts on this subject based on the ideXlab platform.
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mutagenicity of a unique thymine thymine dimer or thymine thymine pyrimidine Pyrimidone 6 4 photoproduct in mammalian cells
Nucleic Acids Research, 1996Co-Authors: Annabelle Gentil, Le F Page, A Margot, Angela Borden, Christopher W. Lawrence, Alain SarasinAbstract:The mutagenic properties of UV-induced photoproducts, both the cis-syn thymine-thymine dimer (TT) and the thymine-thymine pyrimidine Pyrimidone (6-4) photoproduct [T(6-4)T] were studied in mammalian cells using shuttle vectors. A shuttle vector able to replicate in both mammalian cells and bacteria was produced in its single-stranded DNA form. A unique photoproduct was inserted at a single restriction site and after recircularization of the single-stranded DNA vector, this latter was transfected into simian COS7 cells. After DNA replication the vector was extracted from cells and used to transform bacteria. Amplified DNA was finally analyzed without any selective screening, DNA from randomly picked bacterial colonies being directly sequenced. Our results show clearly that both lesions are mutagenic, but at different levels. Mutation frequencies of 2 and 60% respectively were observed with the TT dimer and the T(6-4)T. With the TT dimer the mutations were targeted on the 3'-T. With the T(6-4)T a large variety of mutations were observed. A majority of G-->T transversions were semi-targeted to the base before the 5'-T of the photoproduct. These kinds of mutations were not observed when the same plasmid was transfected directly into SOS-induced JM105 bacteria or when the T(6-4)T oligonucleotide inserted in a different plasmid was replicated in SOS-induced SMH10 Escherichia coil bacteria. These semi-targeted mutations are therefore the specific result of bypass of the T(6-4)T lesion in COS7 cells by one of the eukaryotic DNA polymerases.
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the thymine thymine pyrimidine Pyrimidone 6 4 ultraviolet light photoproduct is highly mutagenic and specifically induces 3 thymine to cytosine transitions in escherichia coli
Proceedings of the National Academy of Sciences of the United States of America, 1991Co-Authors: J E Leclerc, Angela Borden, Christopher W. LawrenceAbstract:Abstract We have constructed single-stranded, M13-based vectors that contain a specifically located thymine-thymine pyrimidine-Pyrimidone(6-4) UV photoproduct and have used these to estimate the frequency and accuracy of DNA replication past this adduct in uvrA6 cells of Escherichia coli. Both the normal and the Dewar valence photoisomer of the (6-4) adduct were studied. In the absence of SOS induction, vectors carrying the photoproducts were rarely replicated; relative to the lesion-free control, 1.9% of vectors carrying the normal (6-4) isomer produced plaques, and with the Dewar valence isomer the proportion was 0.4%. In SOS-induced cells, these frequencies rose to 22.1% and 12.3%, respectively. The error frequency of replication past the normal isomer in SOS-induced cells was high; in a random sample of 185 progeny phage analyzed, 169 (91%) contained mutations, all of which were targeted. Equally striking, a high proportion of the mutations (158/169; 93%) were of only one type, namely 3' T----C transitions. Both the error frequency and the specificity were much reduced with the Dewar valence isomer; overall, 74/140 (53%) of the phage analyzed were mutant, and of these only 34 (46%) entailed the 3' T----C transition. We speculate that the high error frequency and specificity arise from the formation of a stable T-G base pair, involving hydrogen bonds at O-2 and N-3 in the Pyrimidone ring. Potential hydrogen bonds at these sites are coplanar in the normal but not in the Dewar isomer, perhaps explaining the reduced specificity of mutagenesis with the latter adduct.
M P Kaushik - One of the best experts on this subject based on the ideXlab platform.
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n n dichlorobis 2 4 6 trichlorophenyl urea cc 2 as a new reagent for the synthesis of Pyrimidone and pyrimidine derivatives via biginelli reaction
Tetrahedron Letters, 2011Co-Authors: B N Acharya, Sanjeev K Verma, M P KaushikAbstract:A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of Pyrimidone and pyrimidine derivatives.
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N,N′-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent for the synthesis of Pyrimidone and pyrimidine derivatives via Biginelli reaction
Tetrahedron Letters, 2011Co-Authors: B N Acharya, Sanjeev K Verma, M P KaushikAbstract:A simple and efficient method for the synthesis of 3,4-dihydropyrimidin-2-(1H)one and benzo[4,5]imidazo/thioazo[1,2-a]pyrimidine derivatives has been described using N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2) as a new reagent. This method is found to be efficient and convenient for the synthesis of Pyrimidone and pyrimidine derivatives.