Modifying DNA

Chemical Biology

A new technique that makes it possible to add hydrocarbon chains to DNA in a sequence-specific manner has been developed by a collaborative European group.

Methylation is a common type of chemical derivatization that nature uses to turn genes on and off in cells and to modify biomolecules for other purposes. In the process, catalyzed by numerous methyltransferases, methyl groups are removed from S-adenosyl-L-methionine (AdoMet) at its sulfonium position and placed sequence-specifically in DNA, RNA, and proteins.

To derivatize such biomolecules with greater versatility for a range of functional studies, researchers have tried replacing AdoMet's methyl group with larger hydrocarbons, such as ethyl or propyl groups, and then using methyltransferases to catalyze the transfer of those groups. When that is done, however, reaction rates plummet to impractically low levels.

Now, a collaborative team has discovered a clever chemical end run around this problem: Alkyl groups may not work, but some alkenyl and alkynyl groups do. Methyltransferases accept and transfer to DNA hydrocarbons of up to five carbon units with a double or triple bond one carbon atom away from AdoMet's sulfonium center. The unsaturated bonds in these systems activate the transferring group, the researchers believe, and thus permit the reactions to proceed rapidly and still sequence-specifically.

The DNA derivization approach was developed by Saulius Klimaauskas, Howard Hughes Medical Institute international research scholar and head of the Laboratory of Biological DNA Modification at the Institute of Biotechnology, Vilnius, Lithuania; professor of organic chemistry Elmar Weinhold of RWTH Aachen University, in Germany; and coworkers (Nat. Chem. Biol., published online Nov. 27, dx.doi.org/10.1038/nchembio754). They believe the technique should also work for derivatizing RNA, proteins, and other biomolecules.