Mammalian AlkB homologue 2(ALKBH2)is the primary housekeeping DNA demethylase,effectively repairing endogenously formed methylated lesions in double-stranded DNA.Our previous studies demonstrated that a hydrophobicβ-...Mammalian AlkB homologue 2(ALKBH2)is the primary housekeeping DNA demethylase,effectively repairing endogenously formed methylated lesions in double-stranded DNA.Our previous studies demonstrated that a hydrophobicβ-hairpin motif of ALKBH2 could play crucial roles in base-pair stability interrogation and damaged base flipping.Using chemical cross-linking strategy,we obtained two crystal structures of human ALKBH2 mutant bound to duplex DNA.The structural analysis suggests that theβ-hairpin motif is flexible in conformation and is likely to slide along the DNA duplex in local regions to search for damaged base.This study provides a new mechanistic insight into DNA damage detection by ALKBH2.展开更多
5-Aminolevulinic acid(5-ALA)has been approved for clinical photodynamic therapy(PDT)due to its negligible photosensitive toxicity.However,the curative effect of 5-ALA is restricted by intracellular biotransformation i...5-Aminolevulinic acid(5-ALA)has been approved for clinical photodynamic therapy(PDT)due to its negligible photosensitive toxicity.However,the curative effect of 5-ALA is restricted by intracellular biotransformation inactivation of 5-ALA and potential DNA repair of tumor cells.Inspired by the crucial function of iron ions in 5-ALA transformation and DNA repair,a liposomal nanomedicine(MFLs@5-ALA/DFO)with intracellular iron ion regulation property was developed for boosting the PDT of 5-ALA,which was prepared by co-encapsulating 5-ALA and DFO(deferoxamine,a special iron chelator)into the membrane fusion liposomes(MFLs).MFLs@5-ALA/DFO showed an improved pharmaceutical behavior and rapidly fused with tumor cell membrane for 5-ALA and DFO co-delivery.MFLs@5-ALA/DFO could efficiently reduce iron ion,thus blocking the biotransformation of photosensitive protoporphyrin IX(Pp IX)to heme,realizing significant accumulation of photosensitivity.Meanwhile,the activity of DNA repair enzyme was also inhibited with the reduction of iron ion,resulting in the aggravated DNA damage in tumor cells.Our findings showed MFLs@5-ALA/DFO had potential to be applied for enhanced PDT of 5-ALA.展开更多
基金financially supported by the Hundred Talents Program of the Chinese Academy of Sciences,Key Project of Chinese National Programs for Fundamental Research and Development(2009CB918502)
文摘Mammalian AlkB homologue 2(ALKBH2)is the primary housekeeping DNA demethylase,effectively repairing endogenously formed methylated lesions in double-stranded DNA.Our previous studies demonstrated that a hydrophobicβ-hairpin motif of ALKBH2 could play crucial roles in base-pair stability interrogation and damaged base flipping.Using chemical cross-linking strategy,we obtained two crystal structures of human ALKBH2 mutant bound to duplex DNA.The structural analysis suggests that theβ-hairpin motif is flexible in conformation and is likely to slide along the DNA duplex in local regions to search for damaged base.This study provides a new mechanistic insight into DNA damage detection by ALKBH2.
基金supported by the National Natural Science Foundation of China(Nos.82073395,21904119 and 319009919)Innovation Talent Support Program of Henan Province(No.19HASTIT006,China)+1 种基金Key Scientific Research Projects,Education Department of Henan Province(No.20A350009,China)Key scientific research projects,Science and Technology Department of Henan Province(No.192102310147,China)。
文摘5-Aminolevulinic acid(5-ALA)has been approved for clinical photodynamic therapy(PDT)due to its negligible photosensitive toxicity.However,the curative effect of 5-ALA is restricted by intracellular biotransformation inactivation of 5-ALA and potential DNA repair of tumor cells.Inspired by the crucial function of iron ions in 5-ALA transformation and DNA repair,a liposomal nanomedicine(MFLs@5-ALA/DFO)with intracellular iron ion regulation property was developed for boosting the PDT of 5-ALA,which was prepared by co-encapsulating 5-ALA and DFO(deferoxamine,a special iron chelator)into the membrane fusion liposomes(MFLs).MFLs@5-ALA/DFO showed an improved pharmaceutical behavior and rapidly fused with tumor cell membrane for 5-ALA and DFO co-delivery.MFLs@5-ALA/DFO could efficiently reduce iron ion,thus blocking the biotransformation of photosensitive protoporphyrin IX(Pp IX)to heme,realizing significant accumulation of photosensitivity.Meanwhile,the activity of DNA repair enzyme was also inhibited with the reduction of iron ion,resulting in the aggravated DNA damage in tumor cells.Our findings showed MFLs@5-ALA/DFO had potential to be applied for enhanced PDT of 5-ALA.
