Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Nucleic Acids Research Année : 2023

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

Résumé

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.
Fichier principal
Vignette du fichier
NucleicAcidsRes-2023-gkad837.pdf (3.4 Mo) Télécharger le fichier
Origine Publication financée par une institution
Licence

Dates et versions

hal-04261821 , version 1 (27-10-2023)

Licence

Identifiants

Citer

Eka Putra Gusti Ngurah Putu, Laurent Cattiaux, Thomas Lavergne, Yves Pommier, Sophie Bombard, et al.. Unprecedented reactivity of polyamines with aldehydic DNA modifications: structural determinants of reactivity, characterization and enzymatic stability of adducts. Nucleic Acids Research, 2023, ⟨10.1093/nar/gkad837⟩. ⟨hal-04261821⟩
52 Consultations
35 Téléchargements

Altmetric

Partager

Gmail Mastodon Facebook X LinkedIn More