Histone demethylases

The substrate specificities and known biological roles of the histone demethylases (discovered between 2005 and 2009) are summarised below. 

Two main families of histone demethylases have been identified. The LSD family (EC number 1.14.1 l.Bl) employs a monoamine oxidase mechanism to oxidise methyllysine to an imine (with concomitant reduction of FAD to FADH2), followed by addition of water to give a hemiaminal intermediate, which fragments to achieve demethylation. The JmjC family (EC number 

Associates with Co-REST to repress neuronal-specific genes Demethylates p53 possible role in tumourigenesis 

Mutations associated with cleft lip/palate and mental retardation  

Necessary for androgen-receptor dependent transcription Regulation of self-renewal in ES cells  

Until recently, methylation was considered as a permanent modification of chromatin because of the high thermodynamic stability of the N-CH3 bond. Within recent 

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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... 

Eomeris E, Binda C, Vanoni MA, BattagUoli E, Mattevi A (2005) Human histone demethylase LSDl reads the histone code. J Biol Chem 280 41360-41365 Erye RA (2000) Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273 793—798... 

Another speculation has been put forth. Because the turnover of methyl groups such as the modification on lysine residues is low, ubiquitination of histone N-termini might serve as a signal for proteolysis of methylated histones such that dynamic regulation of the chromatin is possible. Since no histone demethylases have been identified, ubiquitin-mediated proteolysis might be a way to reverse the effects of histone methylation. ... 

Histone methylation is a relatively stable modification with a slow turnover rate. However, there is evidence of methyl group turnover for HeLa H3 [150]. It remains to be shown if this histone demethylase activity is present in transformed, but not normal cells. 

Reversible histone methylation is a highly specific process that is catalyzed by the action of histone methyltransferases (HMTs) and histone demethylases on lysine and arginine residues. Like DNMTs, HMTs employ a SAM cofactor. Lysine can be... 

Lysine specific demethylases have been classified into seven groups named KDMl to KDM7 (KDM for Lysine DeMethylase) [90,91,95]. The KDMl group comprises the first enzyme that has been identified as a lysine specific histone demethylase (LS D1). 

The JmjC-containing histone demethylase (JHDM) family encompasses seven sub-families that comprise approximately 20 members in humans [76, 91, 95]. 

Mimasu, S., Sengoku, T, Fukuzawa, S., Umehara, T. and Yokoyama, S. (2008) Crystal structure of histone demethylase LSDl and tranylcypromine at 2.25 A. Biochemical and Biophysical Research Communications, 366 (1), 15-22. 

Enzymes that cleave off modifications may be assayed by measuring the formation of either the protein or a protein-mimicking substrate or the small molecule produd or byproducts (like acetate for histone deacetylases, or formaldehyde or hydrogen peroxide for histone demethylases). Transferases may generally be screened by measuring the conversion of the cosubstrate or quantitatin the formation of the... 

Agger, K., Christensen, J., Cloos, P.A. and Helin, K. (2008) The emerging functions of histone demethylases. Current Opinion in Genetics ej Development, 18, 1-10. 

Our current knowledge regarding histone methylation stems in large part from the study of histone methyltransferases. Several of these enzymes are essential for development, vdth deregulated expression being linked to human disorders such as cancer [4]. Whereas proteins responsible for methylation of histones have been knovm for almost a decade, enzymes with histone demethylase activity (HDM) have only recently been discovered. Here we summarize our current knowledge regarding histone demethylases with a focus on the demethylation mechanisms, potential roles... 

Figure 13.2 (a) Sequential methylation and demethylation of lysines catalyzed by histone methyl transferases (HMTs) and histone demethylases (HDMs), respectively, (b) Sequential methylation and demethylation of arginines catalyzed by HMTs and HDMs, respectively, leading to symmetric and asymmetric dimethylarginines. 

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