The reason for a large proportion of cellular DNA being a non-coding repetitive sequence—intronic DNA (‘junk' DNA)—remains puzzling, but it might confer an evolutionary advantage by protecting important genes from chemical insults. Cells are exposed to myriad genotoxic insults during their lifetime, but surprisingly few manifest as functional changes (e.g. carcinogenesis); perhaps intronic DNA is the mutation target for carcinogens which might explain the surprisingly low incidence of cancer in human populations exposed to carcinogens every day.Smoking is a good example; it results in exposure to potent mutagens such as benzo[a]pyrene which is metabolised by cytochromes P450 to reactive diol epoxides which alkylate the 2-amino group of DNA guanine residues. These mutations might initiate carcinogenesis if not repaired. The in vitro alkylation rate in [3H]-benzo[a]pyrene-exposed lymphocytes from lung cancer patients is 2 x 10-16 moles/cell/2h1. This means that in 2h 1.2 x 108 benzo[a]pyrene molecules would alkylate DNA; since there are approximately 6.4 × 109 nucleotides in the human genome this represents approximately 2% alkylation of the genome.Cellular DNA repair mechanisms will undoubtedly put right many of these mutations, but some will remain for long enough to be amplified by cell division (i.e. promotion) and thus might lead to cancer. This explains why the cumulative risk of lung cancer to age 75 for smokers (e.g. in the UK = 15.7%) is very much greater (e.g. in the UK, 78-fold) than for non-smokers (e.g. in the UK = 0.2%)2.In addition, O6-methylguanine repair efficiency is reduced in lung cancer patients3 which means that mutations are likely to have a greater impact in these people because they are less efficiently repaired. The fact that cancer patients' cells have an inbuilt inefficiency in DNA repair and that long-term smokers have a regular intake of potent carcinogens would suggest a greater cancer risk for smokers compared to controls than is the case. This points to either DNA repair being very efficient or that the key DNA sequences involved in cancer initiation and promotion are not damaged.It is likely that the majority of the DNA alkylated is intronic DNA because it is a large proportion of total cellular DNA; if this were the case, there would be few physiological consequences which might, in turn, explain the lower than expected cancer risk in smokers. Therefore, Intronic DNA might give cells an evolutionary advantage by mopping up extraneous alkylating capacity so protecting the DNA that codes for proteins with important cell functions. Perhaps this is why intronic DNA evolved; it is an ingenious carcinogen detoxification mechanism.Ian C Shaw Director of Biochemistry & Professor of Toxicology University of Canterbury Christchurch, New Zealand

The reason for a large proportion of cellular DNA being a non-coding repetitive sequence—intronic DNA (‘junk' DNA)—remains puzzling, but it might confer an evolutionary advantage by protecting important genes from chemical insults. Cells are exposed to myriad genotoxic insults during their lifetime, but surprisingly few manifest as functional changes (e.g. carcinogenesis); perhaps intronic DNA is the mutation target for carcinogens which might explain the surprisingly low incidence of cancer in human populations exposed to carcinogens every day.Smoking is a good example; it results in exposure to potent mutagens such as benzo[a]pyrene which is metabolised by cytochromes P450 to reactive diol epoxides which alkylate the 2-amino group of DNA guanine residues. These mutations might initiate carcinogenesis if not repaired. The in vitro alkylation rate in [3H]-benzo[a]pyrene-exposed lymphocytes from lung cancer patients is 2 x 10-16 moles/cell/2h1. This means that in 2h 1.2 x 108 benzo[a]pyrene molecules would alkylate DNA; since there are approximately 6.4 × 109 nucleotides in the human genome this represents approximately 2% alkylation of the genome.Cellular DNA repair mechanisms will undoubtedly put right many of these mutations, but some will remain for long enough to be amplified by cell division (i.e. promotion) and thus might lead to cancer. This explains why the cumulative risk of lung cancer to age 75 for smokers (e.g. in the UK = 15.7%) is very much greater (e.g. in the UK, 78-fold) than for non-smokers (e.g. in the UK = 0.2%)2.In addition, O6-methylguanine repair efficiency is reduced in lung cancer patients3 which means that mutations are likely to have a greater impact in these people because they are less efficiently repaired. The fact that cancer patients' cells have an inbuilt inefficiency in DNA repair and that long-term smokers have a regular intake of potent carcinogens would suggest a greater cancer risk for smokers compared to controls than is the case. This points to either DNA repair being very efficient or that the key DNA sequences involved in cancer initiation and promotion are not damaged.It is likely that the majority of the DNA alkylated is intronic DNA because it is a large proportion of total cellular DNA; if this were the case, there would be few physiological consequences which might, in turn, explain the lower than expected cancer risk in smokers. Therefore, Intronic DNA might give cells an evolutionary advantage by mopping up extraneous alkylating capacity so protecting the DNA that codes for proteins with important cell functions. Perhaps this is why intronic DNA evolved; it is an ingenious carcinogen detoxification mechanism.Ian C Shaw Director of Biochemistry & Professor of Toxicology University of Canterbury Christchurch, New Zealand