Formation of an Adenine-Thymine Photoadduct in the Deoxydinucleoside Monophosphate d(TpA) and in DNA

Sn, Bose; Davies, R. Jeremy H.; Sethi, Satinder K.; McCloskey, J A

doi:10.1126/science.6836308

Cited by 101 publications

(79 citation statements)

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“…Notably, AA and TA were the most abundant dinucleotides other than dipyrimidines in both CPD and 6-4pp libraries, with AA dinucleotides at the beginning of 4% of the reads for both libraries and TA dinucleotides beginning 3% of reads for CPD libraries. Little is known about photoproducts involving purines (Pfeifer 1997), but previous studies detected photoproduct formation in synthetic TA and AA dinucleotides (Bose et al 1983;Gallagher and Duker 1986), consistent with signals we observe from photoproducts formed in genomic DNA. It is possible that the AA and TA dinucleotides present in the CPD and 6-4pp libraries more accurately reflect the UV-induced formation of photoproducts at genomic dinucleotides involving purines, or these could be false positive signals generated by, e.g., photolyase bias in the assay.…”

Section: Discussionsupporting

confidence: 65%

High resolution mapping of modified DNA nucleobases using excision repair enzymes

et al. 2014

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The incorporation and creation of modified nucleobases in DNA have profound effects on genome function. We describe methods for mapping positions and local content of modified DNA nucleobases in genomic DNA. We combined in vitro nucleobase excision with massively parallel DNA sequencing (Excision-seq) to determine the locations of modified nucleobases in genomic DNA. We applied the Excision-seq method to map uracil in E. coli and budding yeast and discovered significant variation in uracil content, wherein uracil is excluded from the earliest and latest replicating regions of the genome, possibly driven by changes in nucleotide pool composition. We also used Excision-seq to identify sites of pyrimidine dimer formation induced by UV light exposure, where the method could distinguish between sites of cyclobutane and 6-4 photoproduct formation. These UV mapping data enabled analysis of local sequence bias around pyrimidine dimers and suggested a preference for an adenosine downstream from 6-4 photoproducts. The Excision-seq method is broadly applicable for high precision, genome-wide mapping of modified nucleobases with cognate repair enzymes.[Supplemental material is available for this article.]Many different modifications of the four primary DNA nucleobases expand the chemical diversity of DNA and have profound effects on genome function. Intrinsic modifications (e.g., 5-methylcytosine and uracil) are integral to genetic and epigenetic regulation. Extrinsic modifications (e.g., pyrimidine dimers and nucleobase oxidation) arise from environmental exposures and can initiate aberrant cell growth or death. A detailed understanding of intrinsic and extrinsic nucleobase modification is necessary for a complete view of genetic and epigenetic regulation, but a global picture of how nucleobase modifications are created, maintained, and repaired, and how their spatial distribution impacts genome function, is lacking.Incorporation of uracil into DNA creates detrimental or beneficial mutations, depending on context. To sustain DNA replication, cells must synthesize or scavenge precursors to accumulate a pool of nucleotide triphosphates. A key step of thymidine triphosphate (TTP) synthesis is catalyzed by thymidylate synthase, which converts dUMP to dTMP using tetrahydrofolate as a methyl donor. One branch of the TTP biosynthetic pathway uses dUTP as an intermediate, which can be incorporated into DNA in the form of A:U base pairs. The upstream production of dUMP is catalyzed by deamination of dCMP by deoxycytidylate deaminase or pyrophosphorolysis of dUTP by the dUTP pyrophosphatase (Dut1). Dut1 is essential for viability and normal nucleotide metabolism: In the absence of Dut1, cells simultaneously accumulate dUTP and deplete TTP pools (Gadsden et al. 1993), causing a futile cycle of uracil incorporation and repair that leads to extensive DNA damage (Kavli et al. 2007).Uracil in DNA is removed by uracil DNA glycosylase (UDG) enzymes, which scan double-stranded DNA for uracil and cleave its glycosidic bond (Krokan et al. 200...

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Section: Discussionsupporting

confidence: 65%

High resolution mapping of modified DNA nucleobases using excision repair enzymes

et al. 2014

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“…We also detected a small amount of the TA* photoproduct (peak 2) (Fig. S3B) (28,29). HPLC peaks 7 and 8 were both assigned as Fig.…”

Section: Nucleotide Composition Of the Trimer And Tetramer Np1 Degradmentioning

confidence: 81%

Photocrosslinking of human telomeric G-quadruplex loops by anti cyclobutane thymine dimer formation

Fang

Gross

et al. 2009

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

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The unusual structural forms of telomere DNA, which protect the ends of chromosomes during replication, may render it vulnerable to unprecedented photodamage, possibly involving nonadjacent bases that are made proximate by folding. The G-quadruplex for the human telomere sequence consisting of a repeating d(T-TAGGG) is one unusual form. Tel22, d[AGGG(TTAGGG)3], forms a basket structure in the presence of Na ؉ and may form multiple equilibrating structures in the presence of K ؉ with hybrid-type structures predominating. UVB irradiation of d[AGGG(TTAGGG)3] in the presence of Na ؉ results in a cis,syn thymine dimer between two adjacent Ts in a TTA loop and a mixture of nonadjacent anti thymine dimers between various loops. Irradiation in the presence of K ؉ , however, produces, in addition to these same products, a large amount of specific anti thymine dimers formed between either T in loop 1 and the central T in loop 3. These latter species were not observed in the presence of Na ؉ . Interloop-specific anti thymine dimers are incompatible with hybrid-type structures, but could arise from a chair or basket-type structure or from triplex intermediates involved in interconverting these structures. If these unique nonadjacent anti thymine dimer photoproducts also form in vivo, they would constitute a previously unrecognized type of DNA photodamage that may interfere with telomere replication and present a unique challenge to DNA repair. Furthermore, these unusual anti photoproducts may be used to establish the presence of G-quadruplex or quadruplex-like structures in vivo.mass spectrometry ͉ photochemistry ͉ nonadjacent dimer ͉ DNA ͉ UV T elomeres are repetitive sequences at the ends of chromosomes that function in concert with telomerase and a number of other proteins to protect the ends of chromosomes from shortening during successive rounds of replication (1-3). The human telomere sequence consists of repeating d(TTAGGG) that may fold into various repeating G-quadruplex structures. Short fragments of the human telomere sequence can exist in a myriad of structures that depend on their sequence and on the cations present (4-7). To date, basket (8, 9), parallel (10), and (3 ϩ 1) structures including hybrid-1 and hybrid-2 (11-14) type G-quadruplex forms have been determined by NMR and crystallography. The oligodeoxynucleotide, d[AGGG(TTAGGG) 3 ] (Tel22), adopts a basket structure in solutions containing Na ϩ (8), whereas in the presence of K ϩ , the predominant intracellular cation, the hybrid-type structures are favored over the basket (11, 13) and/or chair (15) structures (Fig. 1).Recently, we discovered that a highly unusual interstrand-type nonadjacent, anti thymine photodimer (Fig. 2B), previously only found in dried or ethanolic solutions of UVC irradiated DNA (16), can form in aqueous solution. Irradiation of d(GTATCAT-GAGGTGC) with UVB light produced a high yield of cis,anti thymine photodimer between T2 and T7 under slightly acidic conditions (17). This anti photodimer must originate from some folded structur...

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“…Other DNA photoproducts are produced at much lower efficiencies than are dimers and (6-4) photoproducts upon UVB irradiation. Purine-purine covalently linked products, cytosine photohydrates, purine photoproducts, single-stand breaks, and DNA-protein crosslinks have been reported upon irradiation of isolated DNA or intact cells with high UVB doses (Bose et al, 1983;Peak et al, 1987;Gallagher and Duker, 1989;Mitchell et al, 1991). Furthermore, there is also evidence for the induction of 8-OHdG following UVB exposure (Stewart et al, 1996).…”

Section: Uv Irradiation and Dna Damagementioning

confidence: 90%

The Role of H²O²as a Mediator of UVB-induced Apoptosis in Keratinocytes

Chang

Oehrl

Elsner

et al. 2003

Free Radical Research

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Formation of an Adenine-Thymine Photoadduct in the Deoxydinucleoside Monophosphate d(TpA) and in DNA

Cited by 101 publications

References 10 publications

High resolution mapping of modified DNA nucleobases using excision repair enzymes

High resolution mapping of modified DNA nucleobases using excision repair enzymes

Photocrosslinking of human telomeric G-quadruplex loops by anti cyclobutane thymine dimer formation

The Role of H²O²as a Mediator of UVB-induced Apoptosis in Keratinocytes

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Formation of an Adenine-Thymine Photoadduct in the Deoxydinucleoside Monophosphate d(TpA) and in DNA

Cited by 101 publications

References 10 publications

High resolution mapping of modified DNA nucleobases using excision repair enzymes

High resolution mapping of modified DNA nucleobases using excision repair enzymes

Photocrosslinking of human telomeric G-quadruplex loops by anti cyclobutane thymine dimer formation

The Role of H2O2as a Mediator of UVB-induced Apoptosis in Keratinocytes

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The Role of H²O²as a Mediator of UVB-induced Apoptosis in Keratinocytes