The Molecular Basis of Histone Demethylation

The methylation of lysine residues on histone tails--and their subsequent demethylation--is among some of the most important covalent post-translational modifications controlling gene expression. When gene expression goes awry, disease ensues and often this disease is some form of cancer. Thus, an understanding of histone tail modification in nucleosomes is critical in mankind’s attempts to eradicate cancers. This chapter examines our present knowledge of the enzymes that demethylate the lysine residues on histone tails, known as KDMs. The substrate-binding specificities of KDMs are quite diverse. The determinants of their specificity goes beyond just the amino acids involved in recognition and catalysis as observed in KDM crystal structures of their catalytic domains but extend to interactions of their many domains to each other and with other proteins in multicomponent complexes. These aspects of all seven known KDM families are reviewed as well as our present knowledge of their involvement in cancers. Control of their aberrant behavior by design of chemical inhibitors, that have the potential to be powerful cancer fighting drugs, is an expanding human endeavor and is chronicled at the end of the chapter.