Role of somatic cancer mutations in human protein lysine methyltransferases

Abstract

Methylation of lysine residues is an important post-translational modification of histone and non-histone proteins, which is introduced by protein lysine methyltransferases (PKMTs). An increasing number of reports demonstrate that aberrant lysine methylation plays a central role in carcinogenesis that is often correlated with abnormal expression of PKMTs. Recent whole genome and whole transcriptome sequencing projects have also discovered several somatic mutations in PKMTs that frequently appear in various tumors. These include chromosomal translocations that lead to aberrant expression or mistargeting of PKMTs and nonsense or frameshift mutations, which cause the loss of the protein function. Another type of mutations are missense mutations which may lead to the loss of enzyme activity, but may also alter the properties of PKMTs either by changing the product or substrate specificity or by increasing the enzymatic activity finally leading to a gain-of-function phenotype. In this review, we provide an overview of the roles of EZH2, SETD2, NSD family, SMYD family, MLL family and DOT1L PKMTs in cancer focusing on the effects of somatic cancer mutations in these enzymes. Investigation of the effect of somatic cancer mutations in PKMTs is pivotal to understand the general role of this important class of enzymes in carcinogenesis and to improve and develop more individualized cancer therapies.

Keywords: Enzyme mechanism; Histone methylation; Lysine methylation; Protein lysine methyltransferase; Somatic cancer mutations.