DNA Backbone Swaps In Sulfur

A DNA modification that was originally conceived for the toolkits of biochemists and gene therapy researchers occurs naturally in bacteria (Nature Chem. Biol., DOI: 10.1038/nchembio.2007.39). The variation, in which a sulfur atom replaces one of the nonbridging oxygen atoms in a phosphate group that links DNA nucleotides together, is called phosphorothioation and is the first known physiological modification of DNA's backbone.

Microbiologist Zixin Deng and graduate student Lianrong Wang of Shanghai Jiaotong University, in China, and biological chemist Peter C. Dedon and postdoc Shi Chen of MIT unearthed the modification. The researchers confirmed the phosphorothioate's chemical structure through high-performance liquid chromatography and mass spectrometry. Though this is not the first natural appearance of sulfur in nucleic acids, the other cases occur mostly in RNA and involve modification on the heterocyclic bases as opposed to the backbone, Dedon says.

Researchers have been making DNA bearing phosphorothioates for decades. Because this functional group confers stability against nucleases, which are enzymes that cleave DNA's phosphate backbone, it has been useful for biochemical research and for clinical applications. "This result illustrates the principle that, ???If man can do it, then nature has probably already done it long before,' " notes Paul R. Schimmel, a professor of molecular biology and chemistry at Scripps Research Institute.

The newly reported work stems from over a decade of work by Deng, who previously characterized five enzymes that work together to incorporate sulfur into DNA. Many species of bacteria possess these enzymes, Dedon says, but no one has searched for them in higher organisms.

The purpose of the newfound backbone motif is not yet known. Even so, "we are very excited about the implications of this observation," Dedon says. The team suspects that phosphorothioation defends DNA against nucleases, much as methylation of DNA bases does. Phosphorothioation might also control gene expression. "It makes you wonder what other modifications of DNA are out there," comments Richard J. Roberts, chief scientific officer of New England Biolabs, which sells nucleic acids, nucleases, and other biomolecules.