State University of New York at Stony Brook

Carcinogens that are present in the body will be converted into forms that will be able to bind to the DNA. This process is called activation. During activation of carcinogens, the enzyme cytochrome P450 will form electrophilic reactive intermediates that are able to bind to the DNA. This reaction will create adducts (carcinogen and DNA bonded) and will be able to give rise to mutations. 

How do carcinogens affect DNA?

Image Map of Carcinogen Pathway

Polymerases can bypass altered bases with the possibility of base misincorporation. Specialized DNA polymerases have evolved to bypass these various DNA damages(the added carcinogens). For example, in the human genetic disorder xeroderma pigmentosum variant (XPV), the DNA polymerase eta can bypass a template containing a BaP and properly incorporate and adenine. If the DNA adducts are bypassed incorrectly then mutations can arise. This can lead to the creation of a new phenotype and if the growth control genes are involved in the formation of tumors. 

DNA polymerases bypassing altered bases

Most cells will not follow this activation process but will go through detoxification in which cells will take away these adducts. This process will excrete the carcinogen breakdown products in harmless forms. The DNA can be repaired by nucleotide excision repair pathways. This Nucleotide Excision Repair Pathway has 4 main steps. The first step involves DNA damage recognition, then incision on both sides of the damaged DNA lesion and removal of the DNA fragment. After this, new DNA is synthesized and the gap is filled.  The open ends of the DNA are closed and the removal process is complete. 



Steps of Detoxification 

Nicotine and certain tobacco-specific nitrosamines can activate protein kinase B (PKB) and protein kinase A. These are very specific for cytogenic changes. Cigarette smoke can activate EGFR and COX-2 which are important for cell proliferation and other transformation processes. 

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