DNA Damage, Mutagenesis and Cancer

Abstract

A large number of chemicals and several physical agents, such as UV light and γ-radiation, have been associated with the etiology of human cancer. Generation of DNA damage (also known as DNA adducts or lesions) induced by these agents is an important first step in the process of carcinogenesis. Evolutionary processes gave rise to DNA repair tools that are efficient in repairing damaged DNA; yet replication of damaged DNA may take place prior to repair, particularly when they are induced at a high frequency. Damaged DNA replication may lead to gene mutations, which in turn may give rise to altered proteins. Mutations in an oncogene, a tumor-suppressor gene, or a gene that controls the cell cycle can generate a clonal cell population with a distinct advantage in proliferation. Many such events, broadly divided into the stages of initiation, promotion, and progression, which may occur over a long period of time and transpire in the context of chronic exposure to carcinogens, can lead to the induction of human cancer. This is exemplified in the long-term use of tobacco being responsible for an increased risk of lung cancer. This mini-review attempts to summarize this wide area that centers on DNA damage as it relates to the development of human cancer.

Keywords: DNA adduct; carcinogen; carcinogenesis; chronic exposure; metabolism; mutagen; somatic mutation; tumor.

Figure 1

Microsomal metabolic activation of benzo[a]pyrene to its most reactive (+)-anti-B[a]P-7,8-dihydrodiol-9,10-epoxide, which reacts with DNA to form the dG adducts.

Figure 2

The chemical structures of UV light induced cis-syn thymine dimer, pyrimidine(6-4)pyrimidone and Dewar photoproducts formed by two adjacent thymines.

Figure 3

Chemical structures of a few initiating and promoting agents. The initiating agents shown here include polycyclic aromatic hydrocarbons (PAHs) (B[a]P and DMBA, present in soot, coal tar, and many environmental mixtures), nitroaromatic compounds (3-nitrobenzanthrone and 1-nitropyrene, present in diesel exhaust), tobacco-specific nitrosamine (NNK, present in tobacco smoke), an amine salt and a magenta dye (fuchsine), aromatic amine (IQ, formed during cooking of meat), a naturally occurring molecule produced by Aspergillus flavus (AFB₁, a food contaminant), industrial chemicals (vinyl chloride and 1,3-butadiene to make the polymer PVC and synthetic rubber, respectively), lipid peroxidation product (4-HNE, produced in cells and tissues of living organisms or in foods during processing or storage), and a chemotherapeutic agent (MC, a toxic drug used to treat upper gastrointestinal cancers). The promoting agents include the phorbol ester (TPA), benzoyl peroxide, and chrysarobin.

Figure 4

A brief depiction of initiation, promotion, and progression in the process of carcinogenesis.

Figure 5

DNA damage plays a central role in many biological processes linked to cancer.