DNA-Addukt mit 2-Aminofluoren
DNA-Addukt mit Benzpyren

Ein DNA-Addukt ist eine chemisch modifizierte DNA. DNA-Addukte zählen zu den DNA-Schäden.


DNA-Addukte entstehen durch Veränderung der DNA durch verschiedene Mutagene,[1] wie z. B. die Alkylanzien. Dabei wird ein Molekül über eine kovalente Bindung an ein Nukleotid in der DNA gekoppelt. Diese modifizierten Nukleotide stören verschiedene nachfolgende Reaktionen wie die DNA-Replikation einer Zelle. Daher werden DNA-Addukte im Zuge einer DNA-Reparatur erkannt und größtenteils repariert.[2] Bei einer fehlerhaften DNA-Reparatur in Protoonkogenen oder Tumorsuppressorgenen kann ein Tumor entstehen. Die Anzahl an DNA-Addukten in einer Zelle ist ein Maß für die Exposition mit Karzinogenen.[3] Typische Mutagene, die zu DNA-Addukten führen, sind z. B. Safrol, Benzpyrendiolepoxid, Acetaldehyd,[4] Formaldehyd, Vinylchlorid, Ethylenoxid[5] sowie Peroxide von Lipiden und deren Reaktionsprodukte (Malondialdehyd).[6] In einer Untersuchung hatten Personen, bei denen Aflatoxin (AFB1-N7-G) DNA-Addukte nachgewiesen wurden, ein 9,1-fach erhöhtes Risiko an Leberkrebs zu erkranken.[7]


  1. J. C. Delaney, J. M. Essigmann: Biological properties of single chemical-DNA adducts: a twenty year perspective. In: Chemical research in toxicology. Band 21, Nummer 1, Januar 2008, S. 232–252, doi:10.1021/tx700292a, PMID 18072751, PMC 2821157 (freier Volltext).
  2. M. Bichara, M. Meier, J. Wagner, A. Cordonnier, I. B. Lambert: Postreplication repair mechanisms in the presence of DNA adducts in Escherichia coli. In: Mutation research. Band 727, Nummer 3, 2011 May-Jun, S. 104–122, doi:10.1016/j.mrrev.2011.04.003, PMID 21558018.
  3. D. K. La, J. A. Swenberg: DNA adducts: biological markers of exposure and potential applications to risk assessment. In: Mutation research. Band 365, Nummer 1–3, September 1996, S. 129–146, PMID 8898994.
  4. T. R. Rajalakshmi, N. AravindhaBabu, K. T. Shanmugam, K. M. Masthan: DNA adducts-chemical addons. In: Journal of pharmacy & bioallied sciences. Band 7, Suppl 1April 2015, S. S197–S199, doi:10.4103/0975-7406.155901, PMID 26015708, PMC 4439668 (freier Volltext).
  5. J. A. Swenberg, K. Lu, B. C. Moeller, L. Gao, P. B. Upton, J. Nakamura, T. B. Starr: Endogenous versus exogenous DNA adducts: their role in carcinogenesis, epidemiology, and risk assessment. In: Toxicological sciences : an official journal of the Society of Toxicology. Band 120 Suppl 1, März 2011, S. S130–S145, doi:10.1093/toxsci/kfq371, PMID 21163908, PMC 3043087 (freier Volltext).
  6. D. Pluskota-Karwatka: Modifications of nucleosides by endogenous mutagens-DNA adducts arising from cellular processes. In: Bioorganic Chemistry. Band 36, Nummer 4, August 2008, S. 198–213, doi:10.1016/j.bioorg.2008.04.002, PMID 18561974.
  7. M. C. Poirier: DNA adducts as exposure biomarkers and indicators of cancer risk. In: Environmental Health Perspectives. Band 105, Nr. 4, 1997, PMID 9255579.

Auf dieser Seite verwendete Medien

DNA damaged by carcinogenic 2-aminofluorene AF.jpg

Structures of DNA damaged by the carcinogenic aromatic amine 2-aminofluorene (AF). Left: AF in the B-DNA major groove, the predominant structure at a mutational coldspot. Right: AF inserted into the helix with displacement of the damaged guanine, the predominant structure at a mutational hotspot. Color code: AF: blue; AF-damaged guanine: yellow; cytosine partner to damaged guanine: gray.

Molecular Understanding of Mutagenicity Brian E. Hingerty, Oak Ridge National Laboratory Suse Broyde, New York University Dinshaw J. Patel, Memorial Sloan Kettering Cancer Center

Research Objectives

To elucidate why certain DNA base sequences are mutational hotspots when damaged by carcinogenic environmental chemicals.

Computational Approach

Molecular mechanics calculations in combination with data from NMR experiments in the form of distances between hydrogens on the carcinogen-damaged DNA molecule are employed to produce molecular views of the damaged DNA that are in agreement with the data. The computations are carried out with the molecular mechanics program DUPLEX on the Cray C90.


The aromatic amines are a category of environmental carcinogens present in tobacco smoke, automobile exhaust, dyes and other industrial products, and broiled meats and fish. These substances, when activated biochemically, can bind to DNA and subsequently cause a mutation when the DNA replicates. Such mutations are widely believed to be the initiating event in carcinogenesis by these substances. Often, the target base in the DNA to which the carcinogen binds is guanine (G). Interestingly, it has been found that a carcinogen-bound guanine may be highly mutagenic (a hotspot) or weakly or non-mutagenic, depending on what the neighbor bases are. One example of such a sequence that has been of considerable interest comes from the E. coli bacterium. It is known as the NarI sequence and contains the bases G1-G2-C-G3, where C is the base cytosine. Surprisingly, G3 is a mutational hotspot when bound by certain aromatic amine carcinogens while G1 and G2 are not. The underlying reason for this difference has been a mystery and is of great importance because it is a paradigm for mutational hotspots, such as in the p53 gene, which are found mutated in many human tumors.

We have elucidated the structure of a DNA duplex containing the NarI sequence linked at G1, G2, or G3 with a model aromatic amine carcinogen known as 2-aminofluorene (AF), using a combination of high-resolution NMR solution studies and molecular mechanics computations. These studies have revealed a striking difference in structure when the carcinogen damage is at G3, compared to G1 or G2. When the AF is at G1 or G2, it resides preponderantly in the major groove of an unperturbed B-DNA double helix. However, when the AF is at G3, it resides half the time in a position where it is inserted into the helix, causing the damaged guanine to be displaced from its normal helix-inserted position. It is plausible that this structural distortion, if also present during DNA replication in the cell, could be responsible for the failure of the DNA to replicate normally when the hotspot is damaged, leading to the mutatagenic consequence.


This work is the first delineation of structural distinctions between mutagenic hotspots and coldspots, revealing how subtle differences in base sequence can produce remarkable differences in structure that can explain the hotspot phenomenon.


Mao B., Gu Z., Hingerty B. E., Broyde S. and Patel D. J. N. d. Solution structure of the aminofluorene [AF]-intercalated conformer of the syn [AF]-C8-dG adduct opposite dC in a DNA duplex. Biochemistry, In Press.

Mao B., Gu Z., Hingerty B. E., Broyde S. and Patel D. J. N. d. Solution structure of the aminofluorene [AF]-external conformer of the anti [AF]-C8-dG adduct opposite dC in a DNA duplex. Biochemistry, In Press.