Histones Lysine

ENZYME MECHANISM AND CATALYSIS OF HISTONE LYSINE METHYLATION [49,50]... 

In addition to histone deacetylation, histone lysine methylation can also lead to gene silencing which is not blocked by the HDAC inhibitors [6, 51], Several lines of evidence have suggested a connection between cancer and histone lysine methyltrans-ferases (HKMTs) [52], HKMTs catalyze the transfer of methyl group(s) from the cofactor. S -adenosyI-methionine (AdoMet) to some specific lysine residues in the N-terminal histone tails [53, 54], With one exception of Dotl [55], all known HKMTs contain the SET domain which represents a novel structural fold [53, 56], Among SET-domain HKMTs, SET7/9 is one of the best characterized experimentally. It is a... 

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... 

Hu P, Zhang Y (2006) Catalytic mechanism and product specificity of the histone lysine methyl-transferase set7/9 An ab initio QM/MM-FE study with multiple initial structures. J Am Chem Soc... 

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... 

Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol 6 838-849... 

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

Kwon T, Chang JH, Kwak E, Lee CW, Joachimiak A, Kim YC, Lee JW, Cho Y (2003) Mechanism of histone lysine methyl transfer revealed by the structure of set7/9-adomet. EMBO J., 22 292-303... 

Methylation of histone lysines has been seen only in H3 and H4 at position 9, 27 for H3 and at position 20 of H4. Sometimes a lysine may have more than one methyl group (Ogawa et al., 1969 Patthy et al., 1973 DeLange et al., 1969, 1973). Methylation of histidines was reported for HI and H5 in duck erythroid cells. This modification, which occurs late in S phase or in G, is found in the amino-terminal region of H3 and H4 and is irreversible (for references, see Allfrey, 1977 Dixon, 1976). 

Verschure PJ, van der Kraan I, de Leeuw W, van der Vlag J, Carpenter AE, Belmont AS, van Driel R (2005) In vivo HPl targeting causes large-scale chromatin condensation and enhanced histone lysine methylation. Mol Cell Biol 25 4552-4564... 

Whetstine JR, Nottke A, Lan F, Huarte M, Smolikov S, Chen Z, Spooner E, Li E, Zhang G, Colaiacovo M et al (2006) Reversal of histone lysine trimethylation by the JMJD2 family of histone demethylases. Cell 125 467 81... 

Markham D, Munro S, Soloway J, O Connor DP, La Thangue NB (2006) DNA-damage-responsive acetylation of pRb regulates binding to E2F-1. EMBO Rep.7(2) 192-198 Martin C, Zhang Y (2005) The diverse functions of histone lysine methylation. Nat Rev Mol Cell Biol. 6(11) 838-849... 

Figure 4. Possible deposition timing of histone lysine methylation...

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... 

Kubicek S, Jenuwein T (2004) A crack in histone lysine methylation. Cell 119 903-906 Kwon HJ, Kim JH, Kim M, Lee JK, Hwang WS, Kim DY (2003) Anti-parasitic activity of depudecin on Neospora caninum via the inhibition of histone deacetylases. Vet Parasitol 112 269-276 Lau OD, Kundu TK, Soccio RE, Ait-Si-Sli S, Khail EM, Vassilev A, Wolffe AP, Nakatani Y, Roeder RG, Cole PA (2000) HATs off Selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. Mol Cell 5 589-595... 

Methylation plays an important role in transcriptional regulation and a lesser role in signal transduction. " Histones are heavily methylated proteins. Single, double, or triple methylated lysines play an important role on histones. Lysine methylation is a more subtle transcriptional control than acetylation. Lysine methylation has come to light in another protein known as p53. p53 is a protein expressed in low levels in the cell and stabilized by posttranslational modifications including phosphorylation, acetylation, and now N-methylation. There are several C-terminal lysines on p53 that increase its stability. The addition of the methylation modifications adds complexity to p5 3 and fine-tunes its activity and ultimately suppresses tumor formation. ... 

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... 

Litt, M.D., Simpson, M., Gaszner, M., Allis, C.D., and Felsenfeld, G. (2001) Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus. Science 293, 2453-2455. 

Histone deacetylases (HDAGs) catalyze the removal of acetyl groups from the Ne atom of histone lysines in a nucleosomal context, ensuring the reversibility of histone acetylation. Histone deacetylation is often associated vdth transcriptional repression and silencing since it promotes chromatin higher order structures and the recruitment of silencers [34]. As other enzymes involved in chromatin... 

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])... 

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