Oxidative Stress and Inflammation Linked to Frameshift Mutations

Cancer researchers have found that malondialdehyde, an endogenous product of oxidative stress, induces sequence-dependent frameshift mutations and base pair substitutions in bacteria and in mammalian cells and may play a role in the development of colorectal cancer in humans.

Malondialdehyde reacts with guanine to form the exocyclic adduct, pyrimido[1,2-alpha]purin-10(3H)-one (M1G). Investigators at Vanderbilt University (Nashville, TN, USA) constructed DNA molecules with M1G inserted at different positions in the nucleotide sequence. These molecules were inserted into both Escherichia coli and mammalian COS-7 kidney cells. After the cells divided, the DNA was recovered from the new cells and examined for mutations. The results, published in the November 5, 2003, online edition of the Proceedings of the [U.S.] National Academy of Sciences, revealed that M1G induced sequence-dependent frameshift mutations and base pair substitutions in both the bacteria and the mammalian cells.

"A number of studies have implicated chronic inflammation in the development of cancers, but the specific way that occurs is not clear,” explained senior author Dr. Lawrence J. Marnett, director of the Hancock Research Center at Vanderbilt University. "These studies suggest a direct link between oxidative stress, like that seen in chronic inflammation, and genetic mutations that cause human disease.”




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