A histone H3K9M mutation traps histone methyltransferase Clr4 to prevent heterochromatin spreading

Cells switch their genes on or off in order to respond to changes in their environment. A group of proteins called histones are partly responsible for regulating gene activity. Like all proteins, histones are made from smaller building blocks called amino acids. Enzymes can chemically modify specific amino acids in histone proteins, which allows the histones to switch nearby genes on or off. One of these modifications is called methylation, and the methylation of specific “lysine” amino acids in histone proteins regulates gene activity in different ways. Previous research has shown that, in certain types of cancer cells, lysines that can be methylated are often replaced with another amino acid, a methionine. These substitutions stop the histones from correctly controlling the activity of nearby genes because methionine cannot be methylated like lysine. Additionally, even if only a small number of histones have methionine in place of lysine, this change can have a widespread effect because the few histones with the methionine can block other histones from being methylated too. However, previous studies did not provide a clear mechanism for why this is the case. In the fission yeast Schizosaccharomyces pombe an enzyme called Clr4 methylates a histone protein at a lysine named H3K9. Now, Shan, Wang, Xu et al. show that substituting this lysine with a methionine (referred to as H3K9M) stops the widespread methylation of histones by trapping the Clr4 enzyme. Specifically, Clr4 becomes stuck to the H3K9M histones, and is therefore unable to modify any other histones. Shan et al. went on to carry out a more detailed study of the structure of H3K9M attached to another enzyme called G9a. This enzyme is found in human cells and is similarly inhibited by H3K9M. This investigation identified additional chemical interactions that explain why Clr4 and G9a become trapped by the H3K9M histone but not by normal histones. Future studies are needed to explore whether other altered histones are able to trap enzymes in the way that H3K9M traps Clr4 and G9a. In addition, this work could eventually lead to new cancer therapies.