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Interaction of bulky chemical carcinogens with DNA in chromatin
1Department of Carcinogenesis, University of Texas MD Anderson Cancer Center, Smithville 78957, USA.
Abstract:
DNA damage is an important effect of treatment of cells and organisms with chemical carcinogens. Although much has been learned from in vitro studies of the reaction of carcinogens with purified DNA, in vivo the DNA is associated with a variety of histone and non-histone proteins in a complex and dynamic structure known as chromatin. The covalent interactions of bulky chemical carcinogens with chromatin are reviewed. Differences from bulk genomic DNA in adduct density are found in replicating, transcribing and nuclear matrix-bound DNA regions, and between DNA in nucleosome cores and linker DNA regions. These differences range from 2- to 3-fold for linker versus core, to approximately 8-fold close to a replication fork. Much remains to be done to determine the influences of non-histone proteins and higher order chromatin structure on carcinogen binding.
Insights
Chemical carcinogens cause DNA damage in vivo. Carcinogen binding to DNA varies within chromatin, differing in replicating, transcribing, and nuclear matrix-bound regions.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Chemical carcinogens induce DNA damage, a critical factor in cancer development.
- In vitro studies reveal carcinogen reactions with purified DNA, but in vivo, DNA exists within chromatin.
- Chromatin is a dynamic structure of DNA and proteins (histone and non-histone).
Purpose of the Study:
- To review the covalent interactions of bulky chemical carcinogens with chromatin.
- To highlight differences in carcinogen binding within various DNA regions and chromatin structures.
Main Methods:
- Review of existing literature on chemical carcinogen interactions with chromatin.
- Analysis of adduct density differences in specific DNA regions (replicating, transcribing, nuclear matrix-bound).
- Comparison of adduct density between nucleosome core DNA and linker DNA.
Main Results:
- Carcinogen binding density varies significantly across different DNA regions within chromatin.
- Adduct density differences observed in replicating, transcribing, and nuclear matrix-bound DNA.
- DNA in linker regions shows 2- to 3-fold higher adduct density than in nucleosome cores.
- Regions near replication forks exhibit approximately 8-fold higher adduct density.
Conclusions:
- In vivo, chemical carcinogen interactions with DNA are influenced by chromatin structure.
- Significant variations in carcinogen adduct density exist within chromatin, affecting DNA regions differently.
- Further research is needed to understand the roles of non-histone proteins and higher-order chromatin structure in carcinogen binding.