2′-Fluorinated Hydantoins as Chemical Biology Tools for Base Excision Repair Glycosylases

Cao, Sheng; Rogers, JohnPatrick; Yeo, Jongchan; Anderson-Steele, Brittany; Ashby, Jonathan; David, Sheila S.

doi:10.1021/acschembio.9b00923

Cited by 6 publications

(4 citation statements)

References 74 publications

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“…Structural studies of Ed and UE NEIL1 bound to a Tg duplex showed that the Lys242 or Arg242 side chain, within the lesion recognition loop of NEIL1, interacts with the Tg base . However, the two isoforms exhibited similar affinity in electrophoretic mobility shift assays (EMSAs) to duplex DNA-containing noncleavable synthetic analogues, 2′-fluorothymidine glycol (FTg) and 2′F-guanidinohydantoin (FGh). , These results suggested that the origin of the differential lesion processing is related to a kinetic step rather than lesion binding affinity. The biological implications of NEIL1 recoding have not been fully elaborated; however, conspicuously, multiple myeloma cells overexpressing Ed NEIL1 proliferated at significantly higher rates and presented hallmark signatures associated with unrepaired double-strand breaks …”

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confidence: 99%

NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision

et al. 2022

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A-to-I RNA editing is widespread in human cells but is uncommon in the coding regions of proteins outside the nervous system. An unusual target for recoding by the adenosine deaminase ADAR1 is the pre-mRNA of the base excision DNA repair enzyme NEIL1 that results in the conversion of a lysine (K) to arginine (R) within the lesion recognition loop and alters substrate specificity. Differences in base removal by unedited (UE, K242) vs edited (Ed, R242) NEIL1 were evaluated using a series of oxidatively modified DNA bases to provide insight into the chemical and structural features of the lesion base that impact isoform-specific repair. We find that UE NEIL1 exhibits higher activity than Ed NEIL1 toward the removal of oxidized pyrimidines, such as thymine glycol, uracil glycol, 5-hydroxyuracil, and 5-hydroxymethyluracil. Gas-phase calculations indicate that the relative rates in excision track with the more stable lactim tautomer and the proton affinity of N3 of the base lesion. These trends support the contribution of tautomerization and N3 protonation in NEIL1 excision catalysis of these pyrimidine base lesions. Structurally similar but distinct substrate lesions, 5-hydroxycytosine and guanidinohydantoin, are more efficiently removed by the Ed NEIL1 isoform, consistent with the inherent differences in tautomerization, proton affinities, and lability. We also observed biphasic kinetic profiles and lack of complete base removal with specific combinations of the lesion and NEIL1 isoform, suggestive of multiple lesion binding modes. The complexity of NEIL1 isoform activity implies multiple roles for NEIL1 in safeguarding accurate repair and as an epigenetic regulator.

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Section: Introductionmentioning

confidence: 99%

NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision

et al. 2022

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“…23,24 The introduction of F atoms to the sugar of DNA has a large impact on DNA stability and activity as the modification of the sugar moiety affects the electronegativity of the base through the stereoelectronic effect. 25,26 Therefore, we speculate that Fsubstituted bases have a strong adsorption capacity on the surface of AuNPs. To evaluate the effect of F atoms on Au/ FDNA stability, a series of Au/F x DNA (x = 1, 2, 3) were prepared (Scheme 1, Scheme 2, Figure S1, and Table 1).…”

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confidence: 96%

Spherical Nucleic Acid Probe Based on 2′-Fluorinated DNA Functionalization for High-Fidelity Intracellular Sensing

et al. 2022

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Traditional spherical nucleic acids (SNAs) based on gold nanoparticles (AuNPs) assembled through Au−S covalent bonds are widely used in DNA-programmable assembly, biosensing, imaging, and therapeutics. However, biological thiols and other chemical substances can break the Au−S bonds and cause response distortion during the application process, specifically in cell environments. Herein, we report a new type of SNAs based on 2′-fluorinated DNA-functionalized AuNPs with excellent colloidal stability under high salt conditions (up to 1 M NaCl) and over a broad pH range (1−14), as well as resistance to biothiols. The fluorinated spherical nucleic acid probe (Au/FDNA probe) could detect targeted cancer cells with high fidelity. Compared to the traditional thiolated DNA-functionalized AuNP probe (Au−SDNA probe), the Au/FDNA probe exhibited a higher sensitivity to the target and a lower signal-to-background ratio. Furthermore, the Au/FDNA probe could discriminate target cancer cells in a mixed culture system. Using the proposed FDNA functionalization method, previously developed SNAs based on AuNPs could be directly adapted, which might open a new avenue for the design and application of SNAs.S pherical nucleic acids (SNAs) based on gold nanoparticles (AuNPs) were first prepared by Chad A. Mirkin and colleagues in 1996, 1 which attracted worldwide interest and opened a new path for the field of bio-nanotechnology. 2−4 These nanomaterials are composed of ultradense nucleic acids with an AuNP core, retaining the recognition functions and programmability of nucleic acid molecules combined with the unique optical, chemical, electrical, and catalytic properties of AuNPs to impart the SNAs with desirable chemical−physical properties and biological functions. 5 Following this, SNAs were widely used in the fields of DNA-programmable assembly, biological analysis, molecular imaging, gene therapeutics, diagnostics, and drug delivery. 6−12 Notably, the thiolated oligonucleotide functionalization of AuNPs prepared through the formation of Au−S bonds has been widely investigated. However, under physiological conditions, the Au−S bond is easily affected by biological thiols, for example, glutathione (GSH) and sulfhydryl ligands, resulting in false-positive signals. 13,14 Therefore, novel SNA alternatives with potentiated stability are urgently needed.In order to avoid the high concentrations of biothiols in living cells, FRET nanoflares were constructed to build a ratiometric fluorescent measurement method that calibrates for nonspecific false-positive signals due to the fracture of the Au− S bond. 14 However, this method fails to address the breakage of Au−S bonds by biothiols. In addition, a selenol-functionalized AuNP probe based on the Au−Se bond has been

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“…This prediction is supported by the finding that both 2′-mono-and difluoro substitutions of deoxyuridine in oligonucleotides prevented glycosylase mediated base excision. 36 Interestingly, some bifunctional glycosylase activities capable of removing the base of a 2′-F-substituted analogue have been detected, 37 but these enzymes could not carry out the required cleavage of the 2′-C−F bond in the arabino-configuration (which would be one of the two fluorines during the subsequent β-elimination step (see Figure S2)), stalling the enzyme at the site of the damage. 37 This is reminiscent of the mechanisms of inactivation of TS and MTase by fluoropyrimidines 31−33 discussed above, which results from the lack of cleavage of the C−F bond in the 5position of the respective substrates (see Figure 6).…”

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confidence: 99%

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine

Kalman

2022

ACS Med. Chem. Lett.

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The structure of the anticancer drug capecitabine was redesigned to prevent metabolic conversion to 5-fluorouracil and its associated potentially fatal toxicities. The resulting cytidine analogue, pencitabine, is a hybrid of capecitabine and gemcitabine, another anticancer drug in clinical use. Preliminary biological evaluation revealed that pencitabine is cytotoxic in vitro in cell culture and orally active in vivo in a human xenograft test system. Pencitabine may mimic the known therapeutically advantageous combination of its parent drugs. Pencitabine is postulated to interfere with DNA synthesis and function by inhibiting multiple nucleotide-metabolizing enzymes and by misincorporation into DNA. Based on detailed mechanistic analyses and literature precedents, the hypothesis is put forward that the significant DNA damage caused by pencitabine may be accounted for by two additional effects not shown by the parent drugs: inhibition of DNA glycosylases involved in base excision repair and of DNA (cytosine-5)-methyltransferase involved in epigenetic regulation of cellular metabolism.

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2′-Fluorinated Hydantoins as Chemical Biology Tools for Base Excision Repair Glycosylases

Cited by 6 publications

References 74 publications

NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision

NEIL1 Recoding due to RNA Editing Impacts Lesion-Specific Recognition and Excision

Spherical Nucleic Acid Probe Based on 2′-Fluorinated DNA Functionalization for High-Fidelity Intracellular Sensing

Rational Design of an Orally Active Anticancer Fluoropyrimidine, Pencitabine, a Hybrid of Capecitabine and Gemcitabine

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