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Updated: Jul 26, 2026
Genome-wide Mapping of Drug-DNA Interactions in Cells with COSMIC (Crosslinking of Small Molecules to Isolate Chromatin)
Published on: January 20, 2016
Covalent binding of polycyclic aromatic compounds to mitochondrial and nuclear DNA
Abstract:
Since the pioneering work of the Millers it has become clear that most chemical carcinogens require metabolism to reactive electrophiles and then exhibit their carcinogenic potential by reacting chemically with, and modifying, cellular macromolecules. At first modification of proteins was considered most likely to be of importance in carcinogenesis. Later, Brookes and Lawley demonstrated that the extent of binding of several polycyclic hydrocarbons to DNA, but not to RNA or protein isolated from the skin of mice treated topically with these compounds, correlated with their known carcinogenic potency to this tissue. Mammalian cells, particularly mouse embryo cells, treated with chemical carcinogens have often been used, and DNA has been involved almost exclusively from whole cells. However, mitochondria possess unique DNA which accounts for 0.1-1% of the total DNA present in mammalian cells, and three studies have shown that carcinogenic alkylating agents modify the michondrial DNA by a factor about five times greater than the nuclear DNA from the same cells. We demonstrate here that with six polycyclic aromatic compounds, all of which require metabolic activation and bind to DNA to a much smaller extent than direct than direct-acting alkylating agents, the binding to mitochondrial relative to DNA is dramatically increased by a factor of nearly 50 to over 500.
Insights
Most chemical carcinogens modify DNA. This study reveals polycyclic aromatic compounds preferentially bind to mitochondrial DNA over nuclear DNA, a key finding for understanding cancer development.
Area of Science:
- Biochemistry
- Molecular Biology
- Toxicology
Background:
- Chemical carcinogens require metabolic activation to exert their carcinogenic effects.
- DNA modification by carcinogens is a critical step in carcinogenesis.
- Mitochondrial DNA is a potential target for chemical carcinogens.
Purpose of the Study:
- To investigate the binding of metabolically activated polycyclic aromatic compounds to mitochondrial DNA versus nuclear DNA.
- To compare the relative binding affinities of polycyclic aromatic compounds to mitochondrial and nuclear DNA.
Main Methods:
- Treatment of mammalian cells with six different polycyclic aromatic compounds.
- Analysis of DNA adducts in both mitochondrial and nuclear DNA fractions.
- Quantification of the relative binding of compounds to mitochondrial DNA compared to nuclear DNA.
Main Results:
- Polycyclic aromatic compounds showed a significantly higher binding affinity to mitochondrial DNA compared to nuclear DNA.
- The relative binding to mitochondrial DNA increased dramatically, ranging from 50 to over 500 times that of nuclear DNA.
- This preferential binding occurred with compounds requiring metabolic activation.
Conclusions:
- Mitochondrial DNA is a significantly preferred target for metabolically activated polycyclic aromatic compounds compared to nuclear DNA.
- This finding highlights the importance of mitochondrial DNA in chemical carcinogenesis.
- Further research into mitochondrial DNA adducts is warranted to understand their role in cancer etiology.
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