Sci. Aging Knowl. Environ., 5 October 2005
Vol. 2005, Issue 40, p. nf79
[DOI: 10.1126/sageke.2005.40.nf79]


Cut the Fat

Enzyme restores lipid-damaged DNA

Mitch Leslie

Fat not only spoils our figures and jams our arteries, but it can also stick to and mar DNA. A new study reports that bacteria tackle this problem by deploying an enzyme that snips off the fatty bits. The work hints that similar enzymes help fend off cancer by tidying our DNA.

Reactive oxygen species, cellular pollutants emitted by metabolism (see "The Two Faces of Oxygen"), can assault DNA directly. But they can also spur indirect damage by attacking lipids, which then adhere to DNA bases, forming etheno adducts. These hangers-on can prevent enzymes from reading a gene or can change a gene's sequence, altering the protein it encodes. Some evidence implicates etheno adducts in cancer. For example, patients with Wilson disease, an overload of copper in the body, carry more adducts than usual and have a higher cancer risk. Cells can fix adducts by snipping out and replacing the damaged DNA base. Toxicologist John Essigmann of the Massachusetts Institute of Technology in Cambridge and colleagues wanted to determine whether cells mobilize other repair mechanisms.

One clue came from previous experiments on bacteria dosed with an adduct-spurring poison. The cells eventually develop resistance to the compound, and one gene whose activity they crank up is AlkB, which can correct other DNA defects by cutting off troublesome methyl groups. To find out whether AlkB prunes adducts, Essigmann and colleagues engineered Escherichia coli to carry a single-stranded molecule of viral DNA sporting the lipid add-ons. In less than 1% of normal bacteria, the adducts changed the DNA's sequence. But that happened in 35% of bugs lacking AlkB, suggesting that they fail to repair the defects. Next, the team used a technique called mass spectrometry, which weighs compounds, to follow the repair reaction. Those results indicate that instead of swapping the disfigured base for a fresh one, AlkB lops off the adduct.

The experiments imply that AlkB spruces up single-stranded DNA, but most of a bacterium's--and a person's--DNA is double-stranded. To discover whether AlkB or a related protein, AlkA, fixes double-stranded DNA, the team exposed cells lacking either enzyme to a compound that induces adducts. Compared with control cells, more AlkB-lacking cells expired--but the death rate was even higher for AlkA-deficient bacteria. That finding hints that AlkA repairs double-stranded DNA, and AlkB handles the single-stranded sections, says Essigmann. Humans harbor eight relatives of AlkB that might protect sections of our genomes that are temporarily single-stranded, including the on-off switches for genes, he says.

"This is a stunning observation," says biochemist Lawrence Marnett of Vanderbilt University in Nashville, Tennessee, because researchers never would have guessed that AlkB was involved in removing adducts. The study is valuable because it identifies a repair mechanism for flaws that potentially provoke tumors in humans, says cancer pharmacologist Ian Blair of the University of Pennsylvania, Philadelphia. Fixing DNA without removing the base is beneficial for cells because it could require less energy and is more accurate, notes free radical biochemist Marcus Cooke of the University of Leicester in the United Kingdom. All three researchers agree we still need to determine whether we have enzymes to keep our DNA fat-free.

October 5, 2005
  1. J. C. Delaney et al., AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo. Nat. Struct. Mol. Biol., 2 October 2005 [e-pub ahead of print]. doi:10.1038/nsmb996
Citation: M. Leslie, Cut the Fat. Sci. Aging Knowl. Environ. 2005 (40), nf79 (2005).

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