Article

DNA condensation by chiral alpha-methylated polyamine analogues and protection of cellular DNA from oxidative damage.

University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Biomacromolecules (impact factor: 5.48). 11/2009; 11(1):97-105. DOI:10.1021/bm900958c
Source: PubMed

ABSTRACT Polyamines are essential molecules supporting the structure, conformation, and function of nucleic acids and proteins. We studied stereoisomers of alpha,alpha'-dimethylated spermine [(R,R)-Me(2)Spm, (S,S)-Me(2)Spm, (R,S)-Me(2)Spm] for their ability to provoke DNA condensation and protect DNA from damage. (R,R)- and (R,S)-Me(2)Spm displayed more efficient condensing ability than spermine, with significantly lower EC(50) (concentration for 50% compaction) values (p < or = 0.01). However, spermine exerted slightly more duplex stabilization than Me(2)Spm. Condensation resulted in nanoparticles with hydrodynamic radii between 39.6 and 48.4 nm, and electron microscopy showed the presence of toroids and spheroids. Natural polyamines and stereoisomers of Me(2)Spm protected DNA against DNase digestion and oxidative stress in vitro and against etoposide and oxidative stress in DU145 cells but afforded little protection against UV-C irradiation. Our findings indicate that Me(2)Spm stereoisomers are efficient DNA packaging agents with potential applications in gene delivery. Our study also reveals stereospecificity in DNA interaction and protection against cellular stress.

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    Trinh T Do, Vicky J Tang, Katie Konigsfeld, Joe A Aguilera, Chris C Perry, Jamie R Milligan
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    ABSTRACT: We have gamma-irradiated plasmid DNA in aqueous solution in the presence of submillimolar concentrations of the ligand tetra-arginine. Depending upon the ionic strength, under these conditions, the plasmid can adopt a highly compacted and aggregated form which attenuates by some two orders of magnitude the yield of damage produced by the indirect effect. The yields of DNA single- and double-strand breaks (SSB and DSB) which result are closely comparable with those produced in living cells. The radical lifetimes, diffusion distances, and track structure are expected to be similarly well reproduced. After irradiation, the aggregation was reversed by adjusting the ionic conditions. The approximate spatial distribution of the resulting DNA damage was then assayed by comparing the increases in the SSB and DSB yields produced by a subsequent incubation with limiting concentrations of the eukaryotic base excision repair enzymes formamidopyrimidine-DNA N-glycosylase (the FPG protein) and endonuclease III. Smaller increases in DSB yields were observed in the plasmid target that was irradiated in the condensed form. By modeling the spatial distribution of DNA damage, this result can be interpreted in terms of a greater extent of damage clustering.
    Biophysik 10/2011; 51(1):43-52. · 1.70 Impact Factor
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Keywords

cellular stress
 
Condensation
 
conformation
 
DNA interaction
 
DNase digestion
 
duplex stabilization
 
efficient condensing ability
 
electron microscopy
 
etoposide
 
hydrodynamic radii
 
Me(2)Spm stereoisomers
 
Natural polyamines
 
nucleic acids
 
oxidative stress
 
Polyamines
 
potential applications
 
provoke DNA condensation
 
stereoisomers
 
UV-C irradiation