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Environmental DNA Damage May Drive Human Mutation

damaged DNA


Mutations drive evolution. Subtle changes in the pairing of the chemical letters of DNA--adenine, cytosine, guanine and thymine--produce new cells with different traits than their ancestors. The fundamental basis of such change is called a single nucleotide polymorphism, or a copying error in the long, chemical book of DNA. Now Japanese researchers have shown how environmentally damaged letters lead to transcription flaws and, ultimately, human diversity.

Ultraviolet light, environmental chemicals, even the by-products of normal cellular metabolism all conspire to continually assault the DNA of humans and every other living thing. Typically, they cause the four chemical precursors to undergo oxidation. For guanine, or G, its oxidized version is called 8-oxoG. When lurking in the area during DNA replication, it bonds with adenine and causes the latter to pair with thymine rather than with its correct partner, unoxidized guanine. This is a permanent change, or mutation.

Geneticist Yusaku Nakabeppu of Kyushu University and his colleagues studied the abundance of 8-oxoG in cellular cultures from four subjects, two men and two women. By fluorescently labeling monoclonal antibodies that attach to DNA sites where 8-oxoG has made its changes the researchers revealed that the oxidized guanine does not occur randomly throughout the chromosome but rather clusters in certain areas.

In fact, 8-oxoG showed a remarkable preference for areas of the chromosome where genetic material was being exchanged and mutations occurred. This preference remained the same for chromosomes from all four subjects, leading Nakabeppu to suggest that 8-oxoG may be responsible for such exchanges and mutations. After all, the clustering of single nucleotide polymorphisms has been observed before, but its cause remains unknown. And that means Nakabeppu and his colleagues may have shown how environmental damage leads to cellular mutation, for good and for ill. The research appears in today's issue of Genome Research.

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