Lysine methylation signaling of non-histone proteins in the nucleus

Abstract

Lysine methylation, catalyzed by protein lysine methyltransferases (PKMTs), is a central post-translational modification regulating many signaling pathways. It has direct and indirect effects on chromatin structure and transcription. Accumulating evidence suggests that dysregulation of PKMT activity has a fundamental impact on the development of many pathologies. While most of these works involve in-depth analysis of methylation events in the context of histones, in recent years, it has become evident that methylation of non-histone proteins also plays a pivotal role in cell processes. This review highlights the importance of non-histone methylation, with focus on methylation events taking place in the nucleus. Known experimental platforms which were developed to identify new methylation events, as well as examples of specific lysine methylation signaling events which regulate key transcription factors, are presented. In addition, the role of these methylation events in normal and disease states is emphasized.

Keywords: Lysine methylation; Methylation signaling; Non-histone methylation; Post-translational modifications (PTMs); Protein lysine methyltransferases (PKMTs).

Fig. 1

Lysine methylation-associated signalling. a Chemical structure of lysine and its methylated derivatives—a hydrogen moiety on the lysine side chain with one (me1), two (me2) or three (me3) methyl groups (shown in red). b The scheme depicts a methylation-associated signalling cascade by which a given PKMT (x, y and z) methylates a repertoire of substrates, which are recognized by different “readers”, which then transduce diverse biological signals

Fig. 2

Detection of lysine methylation. The most common approaches to identify new methylation events are presented. The scheme is divided into candidate-based (top part) and high-throughput (bottom part) experimental platforms (see text for details). A Radioactive in vitro methylation assay in the presence of tritium-labeled SAM (³H), PKMT and a substrate of interest. B Recognition of a methylated substrate with a pan-methyl antibody. C Different assays for the detection of methylated products which rely on the formation of S-adenosylhomocysteine (SAH). D Usage of peptide and protein arrays for screening thousands of potential candidate substrates in an un-biased manner. E Few examples of enrichment steps required for mass spectrometry-based approach (see text for details)

Fig. 3

Lysine methylation signalling mediated by writers, erasers and readers for the transcription factors RelA (a), Erα (b) and HIF1 (c). PKMTs are represented in light gray, erasers are in dark gray and the readers are in purple. The methylated residue numbers are also indicated. Green and red arrows represent a positive or a negative effect on the transcription factor, respectively