Exotic Nucleic Acid Bases

Scientists first thought the human genome was composed of just four DNA bases: adenine, cytosine, guanine, and thymine. But on closer inspection, they discovered that cytosine is sometimes methylated, a decoration that silences genes and thus impacts biochemical processes such as day-to-day gene expression. This year saw the announcement of additional cytosine modifications, in the form of 5-formylcytosine and 5-carboxylcytosine, as well as a flurry of research on 5-hydroxymethylcytosine, which was discovered in human brain cells and stem cells in 2009. Standing out among these developments was work led by Guo-Liang Xu of the State Key Laboratory of Molecular Biology of the Chinese Academy of Sciences and Chuan He of the University of Chicago. Their team discovered how 5-carboxylcytosine and 5-hydroxymethylcytosine are involved in one of the great mysteries in biology, a process called active demethylation (C&EN Online Latest News, Aug. 15; Science, DOI: 10.1126/science.1210944). In the first moments after a sperm fertilizes an egg, cytosine bases on the newly combined DNA are rapidly demethylated to create an embryonic stem cell. But exactly how this occurs had kept scientists guessing. Xu and He found that a family of enzymes called Tet oxidizes 5-methylcytosine to 5-hydroxymethylcytosine and then to 5-carboxylcytosine. They also discovered that a glycosylase enzyme called TDG removes the 5-carboxylcytosine from DNA, activating DNA repair enzymes that then reinsert a cytosine. The research provides the most direct biochemical evidence to date of active demethylation.