Emerging roles of lysine methylation on non-histone proteins

Abstract

Lysine methylation is a common posttranslational modification (PTM) of histones that is important for the epigenetic regulation of transcription and chromatin in eukaryotes. Increasing evidence demonstrates that in addition to histones, lysine methylation also occurs on various non-histone proteins, especially transcription- and chromatin-regulating proteins. In this review, we will briefly describe the histone lysine methyltransferases (KMTs) that have a broad spectrum of non-histone substrates. We will use p53 and nuclear receptors, especially estrogen receptor alpha, as examples to discuss the dynamic nature of non-histone protein lysine methylation, the writers, erasers, and readers of these modifications, and the crosstalk between lysine methylation and other PTMs in regulating the functions of the modified proteins. Understanding the roles of lysine methylation in normal cells and during development will shed light on the complex biology of diseases associated with the dysregulation of lysine methylation on both histones and non-histone proteins.

Keywords: ERα; G9a; Lysine methylation; SETD7; SMYD2; p53.

Fig. 1

Schematic representation of protein structure and posttranslational modifications on p53 and ERα. PTMs are represented by colored dots that are defined in the figure. Protein domains are abbreviated as follows: p53: TAD Transactivation domain, PRD proline-rich domain, DBD DNA-binding domain, TD tetramerization domain, CRD C-terminal regulatory domain; ERα, AF-1 activation function domain 1, DBD DNA-binding domain, LBD ligand-binding domain, AF-2 activation function domain 2; H3, HFD histone fold domain. The first and last amino acids of selected domains are indicated. The protein primary sequence and PTMs of the p53 C-terminal CRD domain, ERα DBD and hinge regions, as well as the histone H3 N-terminal tail, included for comparison, are shown in the zoomed-in boxes. The KMTs catalyzing these lysine methylation events are listed. Residues that are demethylated by LSD1 are also shown

Fig. 2

Crosstalk and functional outcomes of p53 lysine methylation. a SET7-catalyzed monomethylation of p53K372 (K372me1) (activating mark) competes with G9a-catalyzed dimethylation of K373 (K373me2) (repressive mark) to promote the transcriptional activity of p53. b SET7-catalyzed K372me1 (activating mark) competes with SMYD2-catalyzed K370me1 (repressive mark) to promote the transcriptional activity of p53. LSD1 demethylates p53K370me1. c SET8-catalyzed K382me1 (repressive mark) competes with p300-catalyzed K382 acetylation (K382ac) (activating mark) to repress the transcription activity of p53. d L3MBTL1 recognizes p53K382me1 to repress p53 target gene expression. Upon DNA damage, 53BP1 recognizes the dual marks of p53K370me2 and p53K382me2 to act as a transcriptional coactivator of p53. e Dual methylation of p53 K370me2 and K382me2 recruits the PHF20 dimer to inhibit MDM2-mediated p53 ubiquitylation and degradation, thus promoting p53 protein stability and transcription activity

Fig. 3

Crosstalk and functional outcomes of ERα lysine methylation. a SET7-catalyzed ERαK302me1 (activating mark) promotes ERα protein stability and transcriptional activity. The breast cancer-associated K303R mutation inhibits ERαK302me1. b SMYD2-catalyzed K266me1 (repressive mark) competes with the p300-catalyzed K266ac (activating mark) to repress the transcription activity of ERα. LSD1 demethylates K266me1. c G9a-mediated ERα methylation of ERα recruits PHF20 to promote the transcriptional activity of ERα. d EZH2-mediated RORα K38 methylation is recognized DCAF1, which facilitates the CUL4–DDB1-dependent ubiquitination and protein degradation, resulting in a loss of transcriptional activation of RORα