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Preferential targeting of oxidative base damage to internucleosomal DNA
H Enright1, W J Miller, R Hays
1Department of Medicine, University of Minnesota Medical Center, Minneapolis 55455, USA.
Carcinogenesis
|May 1, 1996
Summary
Physiologic iron chelates like iron-ADP specifically damage internucleosomal DNA, not nucleosomal DNA. This targeted oxidative DNA damage may explain iron-dependent mutagenesis and carcinogenesis.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Nuclear chromatin structure influences DNA accessibility to damaging agents.
- Oxidative DNA damage is implicated in mutagenesis and carcinogenesis.
- Physiologically relevant iron chelates play a role in oxidative stress.
Purpose of the Study:
- To investigate the site-specificity of oxidative DNA damage induced by iron-ADP.
- To compare the DNA damaging effects of iron-ADP with iron-EDTA.
- To elucidate the role of iron chelates in iron-dependent oxidative mutagenesis.
Main Methods:
- Studying oxidative DNA strand cleavage mediated by iron-ADP.
- Analyzing the distribution of 8-hydroxydeoxyguanosine (8-OHdG) adducts.
- Comparing DNA modification in nucleosomal versus internucleosomal DNA.
- Utilizing iron-EDTA as a control for fluid-phase radical generation.
Main Results:
- Histone-associated nucleosomal DNA is protected from iron-ADP-mediated damage.
- Internucleosomal DNA is susceptible to oxidative damage by iron-ADP.
- Iron-ADP preferentially targets internucleosomal DNA, showing a 3.5-fold increase in oxidative modification.
- Iron-EDTA does not exhibit site-specific targeting of internucleosomal DNA.
Conclusions:
- Physiologic iron chelates like iron-ADP promote site-specific DNA damage.
- Targeted internucleosomal DNA damage by iron-ADP is relevant to iron-dependent oxidative mutagenesis.
- These findings contribute to understanding mechanisms of carcinogenesis involving iron.