Saccharomyces cerevisiae apurinic/apyrimidinic endonuclease 1 repairs abasic site-mediated DNA-peptide/protein cross-links

Bryan, Cameron; Le, Jennifer; Wei, Xiaoying; Yang, Kun

doi:10.1016/j.dnarep.2023.103501

Cited by 2 publications

(2 citation statements)

References 46 publications

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“…Recently, Yang et al. demonstrated that both APE1 and TDP1 were able to remove the oxime-type adduct of 3′-PUA with an aminooxy analogue of lysine ( 86 , 87 ); moreover, TDP1 was also able to remove a Michael-type DPC formed through the reaction of 3′-PUA with cysteine residue of ALKBH1 ( 88 ). Both these adducts are related to ribodiazepane AP-X adducts since they arise from the 3′-PUA intermediate upon cleavage of AP sites.…”

Section: Resultsmentioning

confidence: 99%

Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts

Gusti Ngurah Putu,

Cattiaux,

Lavergne

et al. 2023

Nucleic Acids Research

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Apurinic/apyrimidinic (AP) sites, 5-formyluracil (fU) and 5-formylcytosine (fC) are abundant DNA modifications that share aldehyde-type reactivity. Here, we demonstrate that polyamines featuring at least one secondary 1,2-diamine fragment in combination with aromatic units form covalent DNA adducts upon reaction with AP sites (with concomitant cleavage of the AP strand), fU and, to a lesser extent, fC residues. Using small-molecule mimics of AP site and fU, we show that reaction of secondary 1,2-diamines with AP sites leads to the formation of unprecedented 3′-tetrahydrofuro[2,3,4-ef]-1,4-diazepane (‘ribodiazepane’) scaffold, whereas the reaction with fU produces cationic 2,3-dihydro-1,4-diazepinium adducts via uracil ring opening. The reactivity of polyamines towards AP sites versus fU and fC can be tuned by modulating their chemical structure and pH of the reaction medium, enabling up to 20-fold chemoselectivity for AP sites with respect to fU and fC. This reaction is efficient in near-physiological conditions at low-micromolar concentration of polyamines and tolerant to the presence of a large excess of unmodified DNA. Remarkably, 3′-ribodiazepane adducts are chemically stable and resistant to the action of apurinic/apyrimidinic endonuclease 1 (APE1) and tyrosyl-DNA phosphoesterase 1 (TDP1), two DNA repair enzymes known to cleanse a variety of 3′ end-blocking DNA lesions.

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Section: Resultsmentioning

confidence: 99%

Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts

Gusti Ngurah Putu,

Cattiaux,

Lavergne

et al. 2023

Nucleic Acids Research

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“…It should be noted that in addition to DPC MdG , a minor amount (<25%) of DPCs detected from MMS treatment of Chinese hamster lung cells (V79) were attributed to the reaction of AP sites that are formed via depurination of alkylated purines (Scheme ). Recently, additional DPC formation pathways emanating from AP sites have been discovered. − Although SPRTN is involved in the repair of DPCs between AP and the HMCES protein, it is not known whether cross-links between AP sites and other proteins are substrates for the protease as well. , Hence, we cannot rule out cytotoxic contributions by AP-derived DPCs upon MMS treatment. We propose that cells containing defects in DPC repair are profoundly impacted by the formation of approximately 1000 DPC MdG molecules per cell (∼9 DPC MdG /10 8 nt).…”

Section: Discussionmentioning

confidence: 99%

Quantification of Intracellular DNA–Protein Cross-Links with N7-Methyl-2′-Deoxyguanosine and Their Contribution to Cytotoxicity

Wen,

Zhao,

Stingele

et al. 2024

Chem. Res. Toxicol.

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The major product of DNA-methylating agents, N7methyl-2′-deoxyguanosine (MdG), is a persistent lesion in vivo, but it is not believed to have a large direct physiological impact. However, MdG reacts with histone proteins to form reversible DNA−protein cross-links (DPC MdG ), a family of DNA lesions that can significantly threaten cell survival. In this paper, we developed a tandem mass spectrometry method for quantifying the amounts of MdG and DPC MdG in nuclear DNA by taking advantage of their chemical lability and the concurrent release of N7-methylguanine. Using this method, we determined that DPC MdG is formed in less than 1% yield based upon the levels of MdG in methyl methanesulfonate (MMS)-treated HeLa cells. Despite its low chemical yield, DPC MdG contributes to MMS cytotoxicity. Consequently, cells that lack efficient DPC repair by the DPC protease SPRTN are hypersensitive to MMS. This investigation shows that the downstream chemical and biochemical effects of initially formed DNA damage can have significant biological consequences. With respect to MdG formation, the initial DNA lesion is only the beginning.

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Saccharomyces cerevisiae apurinic/apyrimidinic endonuclease 1 repairs abasic site-mediated DNA-peptide/protein cross-links

Cited by 2 publications

References 46 publications

Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts

Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts

Quantification of Intracellular DNA–Protein Cross-Links with N7-Methyl-2′-Deoxyguanosine and Their Contribution to Cytotoxicity

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