Histone lysine methyltransferases

Histone lysine (K) methyltransferase (HKMTs) may lead to mono, di- and trimethy-lation of the E-amino group and the extent of modification at a specific site controls the recruitment of the effector proteins. Two unequally populated folds are presently known the SET domain-containing family and the Dotl family (for a recent review, see Ref. [70]) 

S ETdomain containing H KMTs have been classified according to the presence or absence and the nature of the sequences surrounding the SET domain that are conserved within families [71, 72]. The SET domain has a unique structural fold classified as class V AdoMet-dependent methyltransferase (MTase) [69], characterized by four highly-conserved signature sequences, namely motif I 

Schizosaccharamyces pombe Clr4 and several structures of histone H3 K4-specific methyltransferase SET7/9, SET8/PreSET7 and a viral SET domain protein (referred to as vSET) from Paramecium bursaria chlordla virus 1 (for a recent exhaustive review, see Ref. [74]). 

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With the characterized mechanism, the next key question is the origin of its catalytic power. A prerequisite for this investigation is to reliably compute free energy barriers for both enzyme and solution reactions. By employing on-the-fly Born-Oppenheimer molecular dynamics simulations with the ab initio QM/MM approach and the umbrella sampling method, we have determined free energy profiles for the methyl-transfer reaction catalyzed by the histone lysine methyltransferase SET7/9... 

Wang S, Hu P, Zhang Y (2007) Ab initio quantum mechanical/molecular mechanical molecular dynamics simulation of enzyme catalysis the case of histone lysine methyltransferase set7/9. J Phys Chem B ASAP... 

Schneider R, Bannister AJ, Kouzarides T (2002) Unsafe sets histone lysine methyltransferases and cancer. Trends Biochem Sci 27 396-402... 

Dodge JE, Kang YK, Beppu H, Lei H, Li E (2004) Histone H3-K9 methyltransferase ESET is essential for early development. Mol Cell Biol 24 2478—2486 Duan Z, Zarebski A, Montoya-Durango D, Grimes HL, Horwitz M (2005) Gfil coordinates epigenetic repression of p21Cip/WAFl by recruitment of histone lysine methyltransferase G9a and histone deacetylase 1. Mol Cell Biol 280 13928-13935... 

Histone-lysine methyltransferases are chromatin-bound enzymes that catalyses the addition of methyl groups onto lysine or arginine residues of chromatin-bound H3 and H4 [151]. The methyl group is transferred enzymatically to the histone with S-adenosyl methionine as the methyl donor. Histone methylases have been isolated from HeLa S-3 cells [182], chick embryo nuclei [183], and rat brain chromatin [184]. The histone methyltransferases methylated H3 and H4 in nucleosomes [184]. Histone-lysine methyltransferase is a chromatin-bound enzyme [129,151]. Initial characterization of the Tetrahymena macronuclear H3 methyltransferase suggests that the enzyme has a molecular mass of 400 kDa. The enzyme preferred free histones rather than nucleosomes as substrate [138]. More recent studies have now... 

Aniello, F., ColeDa, G., Muscariello, G., Lanza, A., Ferrara, D., Branno, M. and Minucd, S. (2006) Expression of four histone lysine-methyltransferases in parotid gland tumors. Anticancer Research, 26, 2063-2067. 

Zhang X, Yang Z, Khan SI, Horton JR, Tamaru H, Selker EU, et al. Structural basis for the product specificity of histone lysine methyltransferases. Mol. Cell 2003 12 177-185. 

We turn now to histone lysine methyltransferase (HKMT) which catalyzes the methylation of the N-terminal histone tail of chromatin using the 5-adenosyl-methionine (SAM) cofactor as the methylating agent (see Fig. 1). 

SET2 histone lysine methyltransferase encoded from short arm chromosome 3 specific for lysine-36 of histone H3 orthologous to S. cerevisiae interacts with p53 involved in mismatch repair acts as mmor suppressor (kidney carcinoma). Suppressor of variegation Enhancer of zeste Trithorax (drosophila) Dalgliesh GL et al Nature 2010 463 360-363. Li M et al Proc Nad Acad Sci USA 2006 102 17836-17841. 

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