Generation of DNA Interstrand Cross-Links by Post-Synthetic Reductive Amination

Angelov, T.; Guainazzi, Angelo; Schärer, Orlando D.

doi:10.1021/ol802719a

Cited by 71 publications

(111 citation statements)

References 31 publications

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“…Synthesis and Characterization of OligodeoxynucleotidesSynthetic oligonucleotides containing site-specific 7-deaza-7-(2,3-dihydroxypropan-1-yl)-2Ј-deoxyguanosine (5Ј-G TCA CTG GTA deaza-DHP-dGCA AGC ATT G-3Ј and 5Ј-GAA AGA AGdeaza-DHP-dG ACA GAA GAG GGT ACC ATC ATA GAG TCA GTG-3Ј) were prepared as described previously (27). Primers internally labeled with 5Ј-[N-((fluoresceinyl)-aminohexyl)-3-acrylimido]-2Ј-deoxyuridine (5Ј-CAA FAMdTGC TTG-3Ј and 5Ј-CTA TGA FAMdTGG TAC C-3Ј) and native DNA strands (5Ј-G TCA CTG GTA GCA AGC ATT G-3Ј, 5Ј-GAA AGA AGG ACA GAA GAG GGT ACC ATC ATA GAG TCA GTG-3Ј, and 5Ј-CAA TGC TTG-3Ј) were prepared by standard solid phase synthesis using an ABI 394 DNA synthesizer (Applied Biosystems, Foster City, CA).…”

Section: Methodsmentioning

confidence: 99%

“…DNA sequences (5Ј-G TCA CTG GTA XCA AGC ATT G-3Ј and 5Ј-GAA AGA AGX ACA GAA GAG GGT ACC ATC ATA GAG TCA GTG-3Ј where X is the modified base; Table 1) were selected to minimize self-annealing and were used previously in studies of DNA-DNA cross-links (27,28). Two peptides of increasing size, a 10-mer peptide derived from c-Myc protein (EQKLISEEDL) and a 23-mer derived from tetanus toxoid (N 3 (CH 2 ) 3 CO-PDAQLVPGINGKAIHLVNNESSE) were used.…”

Section: Synthesis and Characterization Of Dna-protein And Dna-mentioning

confidence: 99%

“…The replacement of N7-guanine with carbon introduces changes in hydration and charge localization (75). However, 7-deazaguanine-containing DNA has essentially the same structure as native DNA (76), and 7-deazaguanine mimics have been successfully used in a number of previous studies of DNA lesion repair and polymerase bypass (27,(77)(78)(79).…”

Section: 64mentioning

confidence: 99%

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Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Wickramaratne

Mukherjee

et al. 2016

Journal of Biological Chemistry

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DNA-protein cross-links (DPCs) are bulky DNA lesions that form both endogenously and following exposure to bis-electrophiles such as common antitumor agents. The structural and biological consequences of DPCs have not been fully elucidated due to the complexity of these adducts. The most common site of DPC formation in DNA following treatment with bis-electrophiles such as nitrogen mustards and cisplatin is the N7 position of guanine, but the resulting conjugates are hydrolytically labile and thus are not suitable for structural and biological studies. In this report, hydrolytically stable structural mimics of N7-guanine-conjugated DPCs were generated by reductive amination reactions between the Lys and Arg side chains of proteins/peptides and aldehyde groups linked to 7-deazaguanine residues in DNA. These model DPCs were subjected to in vitro replication in the presence of human translesion synthesis DNA polymerases. DPCs containing full-length proteins (11-28 kDa) or a 23-mer peptide blocked human polymerases and . DPC conjugates to a 10-mer peptide were bypassed with nucleotide insertion efficiency 50 -100-fold lower than for native G. Both human polymerase (hPol) and hPol inserted the correct base (C) opposite the 10-mer peptide cross-link, although small amounts of T were added by hPol . Molecular dynamics simulation of an hPol ternary complex containing a template-primer DNA with dCTP opposite the 10-mer peptide DPC revealed that this bulky lesion can be accommodated in the polymerase active site by aligning with the major groove of the adducted DNA within the ternary complex of polymerase and dCTP.

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Section: Methodsmentioning

confidence: 99%

Section: Synthesis and Characterization Of Dna-protein And Dna-mentioning

confidence: 99%

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Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Wickramaratne

Mukherjee

et al. 2016

Journal of Biological Chemistry

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“…We used DNA substrates containing a nitrogen-like ICL, which is free of duplex distortion (15,36,37), …”

Section: Pafan1 Efficiently Incises Icl Lesionmentioning

confidence: 99%

“…1D). We first analyzed ifPaFAN1 can unhook the ICL near the ss/ds junction.We used DNA substrates containing a nitrogen-like ICL, which is free of duplex distortion (15,36,37), The mechanism of ICL unhooking by bacterial FAN1 7 how PaFAN1 can catalyze multiple cleavage events. …”

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confidence: 99%

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

Jin

Roy

Lee

et al. 2018

Journal of Biological Chemistry

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The mechanism of ICL unhooking by bacterial FAN1 4 a "head to tail" dimer in the presence of DNA (34).The authors suggest that FAN1 dimer scans, latches, and unwinds DNA to pull the single-stranded DNA to the active site of a FAN1. Mutations of the residues at the dimeric interface abolished the nuclease activity of the HsFAN1, raising the possibility that the dimerization is important for its activity.Bacterial FAN1 homologs share a high similarity with HsFAN1 (Fig. 1A, 23,35). Second, PaFAN1 does not have a specific basic pocket that is critical for the proposed "3-nt exonuclease" mechanism (Fig. 1B, C, 33). Third, PaFAN1 lacks the basic motif in the SAP domain required for dimerization in one of the structures of the human nuclease (Fig. 1A, 34). These features raise the question if PaFAN1 can unhook ICLs, and if so, by which mechanism.To address these issues, we examined the ICL Based on these findings, we provide insights into how FAN1 might have evolved to have two basic regions to guide its nuclease activity and maintain genomic stability. RESULTS Substrate specificity of PaFAN1In previous study, we have used a DNA substrate with a four nucleotide 5' flap (23). (Fig. S1E-F). PaFAN1 efficiently incises ICL lesionTo examine whether the bacterial FAN1homolog shares the ICL resolving activity of mammalian FAN1, we examined the in vitro ICL unhooking activity of PaFAN1 using various DNA ICL substrates (Fig. 1D). We first analyzed ifPaFAN1 can unhook the ICL near the ss/ds junction.We used DNA substrates containing a nitrogen-like ICL, which is free of duplex distortion (15,36,37), The mechanism of ICL unhooking by bacterial FAN1 7 how PaFAN1 can catalyze multiple cleavage events.

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Synthesis of G‐N²‐(CH₂)₃‐N²‐G Trimethylene DNA Interstrand Cross‐Links

Gruppi

Salyard

Rizzo

2014

CP Nucleic Acid Chemistry

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The synthesis of G-N2-(CH2)3-N2-G trimethylene DNA interstrand cross-links (ICLs) in a 5′-CG-3′ and 5′-GC-3′ sequence from oligodeoxynucleotides containing N2-(3-aminopropyl)-2′-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine is presented. Automated solid-phase DNA synthesis was used for unmodified bases and modified nucleotides were incorporated via their corresponding phosphoramidite reagent by a manual coupling protocol. The preparation of the phosphoramidite reagents for incorporation of N2-(3-aminopropyl)-2′-deoxyguanosine is reported. The high-purity trimethylene DNA interstrand cross-link product is obtained through a nucleophilic aromatic substitution reaction between the N2-(3-aminopropyl)-2′-deoxyguanosine and 2-fluoro-O6-(trimethylsilylethyl)inosine containing oligodeoxynucleotides.

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Generation of DNA Interstrand Cross-Links by Post-Synthetic Reductive Amination

Cited by 71 publications

References 31 publications

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

Synthesis of G‐N²‐(CH₂)₃‐N²‐G Trimethylene DNA Interstrand Cross‐Links

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Generation of DNA Interstrand Cross-Links by Post-Synthetic Reductive Amination

Cited by 71 publications

References 31 publications

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Bypass of DNA-Protein Cross-links Conjugated to the 7-Deazaguanine Position of DNA by Translesion Synthesis Polymerases

Structural mechanism of DNA interstrand cross-link unhooking by the bacterial FAN1 nuclease

Synthesis of G‐N2‐(CH2)3‐N2‐G Trimethylene DNA Interstrand Cross‐Links

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Synthesis of G‐N²‐(CH₂)₃‐N²‐G Trimethylene DNA Interstrand Cross‐Links