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ID 958

Causes, Smoking: "Smoking gun"

Description:
This section reviews K-ras and p53, two genes most frequently mutated in smoking-related lung cancers, one tar component, benzo[a]pyrene, is specifically linked to known mutations in these genes.
Transcript:
“Smoking gun” K-ras and p53 are the two genes most frequently mutated in smoking-related lung cancers. One tar component, benzo[a]pyrene, is specifically linked to known mutations in these genes – providing the equivalent of a "smoking gun" at a murder scene. Within a lung cell, benzo[a]pyrene is converted to an epoxide. The epoxide reacts readily with guanine (G) positions of the DNA helix. If not corrected by the cell's DNA repair mechanism, this guanine “adduct” is misread as a thymine by the DNA polymerase that copies chromosomes during replication. Ultimately, the original G-C base pair may be replaced by a T-A base pair, a mutation called a transversion. Cultured cells treated with benzo[a]pyrene show the same spectrum of G-T transversions as found in the k-ras and p53 genes of smokers. These mutational “hot spots” map well to the guanine binding sites of benzo[a]pyrene expoxide. Benzo[a]pyrene can produce the major known activating mutation in the 12th codon of the K-ras gene. Benzo[a]pyrene can also mutate three key positions in the p53 gene.
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