Lysine and arginine methylation of transcription factors

Abstract

Post-translational modifications (PTMs) are implicated in many biological processes including receptor activation, signal transduction, transcriptional regulation and protein turnover. Lysine's side chain is particularly notable, as it can undergo methylation, acetylation, SUMOylation and ubiquitination. Methylation affects not only lysine but also arginine residues, both of which are implicated in epigenetic regulation. Beyond histone-tails as substrates, dynamic methylation of transcription factors has been described. The focus of this review is on these non-histone substrates providing a detailed discussion of what is currently known about methylation of hypoxia-inducible factor (HIF), P53, nuclear receptors (NRs) and RELA. The role of methylation in regulating protein stability and function by acting as docking sites for methyl-reader proteins and via their crosstalk with other PTMs is explored.

Keywords: Cell cycle; Hypoxia; KDM; KMT; PRMT; PTM.

Fig. 1

Schematic representation of lysine (K) and arginine (R) methylation. The NH₃⁺ group of lysine (K) residues can be methylated by lysine methyltrasferases (KMTs) or demethylated by lysine demethylases (KDMs). Accordingly, to the degree of methylation, it is possible to distinguish three different methylation states: monomethylation (Kme₁) with only one CH₃ group; dimethylation (Kme₂) with two CH₃ groups; trimethylation (Kme₃) with three CH₃ groups. Arginine (R) residues are methylated by meaning of mono- and dimethylation by protein arginine (R) methyltransferases (PRMTs). Arginine monomethylation (indicated as ωMMA) is catalyzed by Type I (PRMT1, 2, 3, 4, 6 and 8), Type II (PRMT5 and 9) and Type III (PRMT7) PRMTs. Arginine dimethylation can occur as symmetrical (indicated as ωsDMA) or asymmetrical (indicated as ωaDMA): Type I catalyze ωaDMA whereas Type II (PRMT5 and 9) catalyze ωsDMA. Type III PRMT catalyze exclusively ωMMA

Fig. 2

Regulation of hypoxia-inducible factor 1-alpha (HIF1α) by lysine (K) and arginine (R) methylation. Under plentiful O₂ concentrations (defined as normoxia), KMT7/SETD7 (lysine methyltransferase 7/SET domain-containing 7) catalyzes hypoxia-inducible factor 1-alpha (HIF1α) monomethylation on K32 (HIF1αK32me₁) and dimethylation on K391 (HIF1αK391me₂) resulting in reduced stability of HIF1α as consequence of increased ubiquitination and degradation. K32me₁ also leads to reduced DNA binding of HIF1α while K391me₂ is associated with increased hydroxylation of HIF1α. Both HIF1αK32me₁ and HIF1αK391me₂ are demethylated by KDM1A/LSD1 (lysine demethylase 1A/lysine-specific histone demethylase 1) leading to increased stability of HIF1α. Under hypoxia, protein arginine (R) methyltransferase 3 (PRMT3) catalyzes asymmetrical dimethylation on R282 (HIF1αR282me_2a) leading to reduced ubiquitination and as consequence increased stability of the protein. KDM1A = KDM1A/LSD1 lysine demethylase 1A/lysine-specific histone demethylase 1; KMT7 = KMT7/SETD7 lysine methyltransferase 7/SET domain-containing 7; PRMT3 protein arginine methyltransferase 3

Fig. 3

Regulation of tumor suppressor P53 by lysine (K) and arginine (R) methylation. Lysine (K) methylation of the tumor suppressor P53 occurs at several lysineresidues located within the regulatory domain (RD). KMT3C/SMYD2 (lysine methyltransferase 3C/ SET and MYND domain-containing 2) monomethylates K370 (P53K370me₁) leading to reduced activity of P53 and apoptosis. An unknown lysine methyltransferase (KMT) further dimethylates K370 (P53K370me₂) which is recognized by Tudor domain-containing proteins [tumor protein P53 binding protein 1 (TP53BP1) or PHD finger protein 20 (PHF20), leading to increased P53 stability and apoptosis. KMT7/SETD7 monomethylates K372 (P53K372me₁) and this supports both the KAT3B/EP300 (lysine acetyltransferase 3B/E1A-binding protein 300 kD)-mediated acetylation on K373 and K382 and the KAT5/TIP60 (lysine acetyltransferase 5/tat interacting protein 60 kDa)-mediated acetylation of P53. Furthermore, KMT7/SETD7-mediated P53K372me₁ reduces the interaction between P53 and KMT3C/SMYD2 and as consequence it reduces the KMT3C/SMYD2-mediated P53K370me₁. As a consequence, P53K372me₁ increases stability of P53 and apoptosis. Both P53K370me₁ and P53K370me₂ are demethylated by KDM1A/LSD1 (lysine demethylase 1A/lysine-specific histone demethylase 1). KMT1C/EHMT2/G9A (lysine methyltransferase 1C/euchromatic histone-lysine N-methyltransferase 2) and KMT1D/EHMT1/GLP (lysine methyltransferase 1D/euchromatic histone-lysine N-methyltransferase 1/G9a-like protein 1) methylate K373 on P53 leading to reduced P53 transcriptional activity and apoptosis. KMT5A/SETD8 (lysine methyltransferase 5A/SET domain-containing 8) monomethylates P53 on K382 (P53K382me₁) reducing acetylation on K382 and acting as a docking site for the methyl binding domains (MBT) of lethal(3)malignant brain tumor-like protein 1 (L3MBTL1) finally leading to reduced P53 transcriptional activity, cell cycle arrest and apoptosis. P53K382me₁ is further dimethylated (P53K382me₂) by unknown KMTs and this post-translation modification (PTM) is further bound by Tudor domain-containing proteins (TP53BP1 or PHF20) increasing stability of P53 and apoptosis. Arginine (R) methylation of P53 occurs on R333 (monomethylation, R333me₁), R335 (symmetric dimethylation, R335me_2s) and R337 (symmetric dimethylation, R337me_2s) and these methylations regulate the target specificity of P53. Green and red boxes indicate methylation events that play a positive or negative role in the P53-dependent response, respectively. Gray box indicates methylation events that regulate the target specificity of P53 response. DBD DNA binding domain; KAT3B = KAT3B/EP300 lysine acetyltransferase 3B/E1A-binding protein 300 kD; KAT5 = KAT5/TIP60 lysine acetyltransferase 5/tat interacting protein 60 kDa; KDM1A = KDM1A/LSD1 lysine demethylase 1A/lysine-specific histone demethylase 1; KDM3A = KDM3A/JMJD1A lysine demethylase 3A/Jumonji domain-containing 1A; KMT1C = KMT1C/EHMT2/G9A lysine methyltransferase 1C/euchromatic histone-lysine N-methyltransferase 2; KMT1D = KMT1D/EHMT1/GLP lysine methyltransferase 1D/euchromatic histone-lysine N-methyltransferase 1/ G9a-like protein 1; KMT3C = KMT3C/SMYD2 lysine methyltransferase 3C/SET and MYND domain-containing 2; KMT5A = KMT5A/SETD8 lysine methyltransferase 5A/SET domain-containing 8; KMT7 = KMT7/SETD7 lysine methyltransferase 7/SET domain-containing 7; L3MBTL1 lethal(3)malignant brain tumor-like protein 1; OD oligomerization domain; PHF20 PHD finger protein 20; PRD proline-rich domain; PRMT5 protein arginine methyltransferase 5; RD regulatory domain; TAD transcriptional activation domain; TP53BP1 tumor protein P53 binding protein 1