Lysine methylation of promoter-bound transcription factors and relevance to cancer

Abstract

p53, NFκB, STAT3, and several other transcription factors are reversibly methylated on lysine residues by enzymes that also modify histones. The methylations of NFκB and STAT3 take place when they are bound to promoters, suggesting a more general model in which the binding of inducible transcription factors to DNA helps to recruit chromatin-modification machinery, which then may modify not only histones but also the bound transcription factors. Mutations of some histone-lysine methyltransferases and demethylases are linked to cancer, and these mutations may alter the methylation not only of histones but also of transcription factors, and thus may be tumorigenic through more than one mechanism.

Figure 1

A model for the kinetics of methylation of chromatin-bound transcription factors by histonemodifying lysine methyltransferases. (A) The transcription factor (TF) and the methyltransferases are free from DNA. (B) The TF binds to its site. (C) The methyltransferases are recruited. (D) The methyltransferases are activated and catalyze methylations of both histones and the TF. Alternatively, some methyltransferases may be pre-associated with some promoters before the TF arrives. Trimethylation of TFs is uncommon, in contrast to the frequent trimethylation of histones. This figure is adapted from Lu and Stark .