Structure of the Catalytic Domain of Human DOT1L, a Non-SET Domain Nucleosomal Histone Methyltransferase

The SUV39 class of methyltransferase enzymes deposits histone H3 lysine 9 di- and trimethylation (H3K9me2/3), the hallmark of constitutive heterochromatin. How these enzymes are regulated to mark specific genomic regions as heterochromatic is poorly understood. Clr4 is the sole H3K9me2/3 methyltransferase in the fission yeast Schizosaccharomyces pombe, and recent evidence suggests that ubiquitination of lysine 14 on histone H3 (H3K14ub) plays a key role in H3K9 methylation. However, the molecular mechanism of this regulation and its role in heterochromatin formation remain to be determined. Our structure-function approach shows that the H3K14ub substrate binds specifically and tightly to the catalytic domain of Clr4, and thereby stimulates the enzyme by over 250-fold. Mutations that disrupt this mechanism lead to a loss of H3K9me2/3 and abolish heterochromatin silencing similar to clr4 deletion. Comparison with mammalian SET domain proteins suggests that the Clr4 SET domain harbors a conserved sensor for H3K14ub, which mediates licensing of heterochromatin formation.

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Ash2 acts as an ecdysone receptor coactivator by stabilizing the histone methyltransferase Trr

Molecular Biology of the Cell ◽

10.1091/mbc.e12-04-0267 ◽

2013 ◽

Vol 24 (3) ◽

pp. 361-372 ◽

Cited By ~ 10

Author(s):

Albert Carbonell ◽

Alexander Mazo ◽

Florenci Serras ◽

Montserrat Corominas

Keyword(s):

Gene Regulation ◽

Histone Modifications ◽

Transcriptional Activation ◽

Histone H3 ◽

Histone Methyltransferase ◽

Ecdysone Receptor ◽

Related Protein ◽

Molting Hormone ◽

Set Domain ◽

Present Evidence

The molting hormone ecdysone triggers chromatin changes via histone modifications that are important for gene regulation. On hormone activation, the ecdysone receptor (EcR) binds to the SET domain–containing histone H3 methyltransferase trithorax-related protein (Trr). Methylation of histone H3 at lysine 4 (H3K4me), which is associated with transcriptional activation, requires several cofactors, including Ash2. We find that ash2 mutants have severe defects in pupariation and metamorphosis due to a lack of activation of ecdysone-responsive genes. This transcriptional defect is caused by the absence of the H3K4me3 marks set by Trr in these genes. We present evidence that Ash2 interacts with Trr and is required for its stabilization. Thus we propose that Ash2 functions together with Trr as an ecdysone receptor coactivator.

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Sinefungin derivatives as small molecule chemical probes of SET domain–containing histone methyltransferase function

Science-Business eXchange ◽

10.1038/scibx.2012.1192 ◽

2012 ◽

Vol 5 (45) ◽

pp. 1192-1192

Keyword(s):

Small Molecule ◽

Histone Methyltransferase ◽

Chemical Probes ◽

Set Domain

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Arabidopsis Histone Methyltransferase SET DOMAIN GROUP8 Mediates Induction of the Jasmonate/Ethylene Pathway Genes in Plant Defense Response to Necrotrophic Fungi

PLANT PHYSIOLOGY ◽

10.1104/pp.110.161497 ◽

2010 ◽

Vol 154 (3) ◽

pp. 1403-1414 ◽

Cited By ~ 107

Author(s):

Alexandre Berr ◽

Emily J. McCallum ◽

Abdelmalek Alioua ◽

Dimitri Heintz ◽

Thierry Heitz ◽

...

Keyword(s):

Plant Defense ◽

Defense Response ◽

Histone Methyltransferase ◽

Plant Defense Response ◽

Set Domain ◽

Necrotrophic Fungi

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Set2 Is a Nucleosomal Histone H3-Selective Methyltransferase That Mediates Transcriptional Repression

Molecular and Cellular Biology ◽

10.1128/mcb.22.5.1298-1306.2002 ◽

2002 ◽

Vol 22 (5) ◽

pp. 1298-1306 ◽

Cited By ~ 356

Author(s):

Brian D. Strahl ◽

Patrick A. Grant ◽

Scott D. Briggs ◽

Zu-Wen Sun ◽

James R. Bone ◽

...

Keyword(s):

Transcriptional Repression ◽

Gene Activation ◽

Limited Information ◽

Set Domain ◽

Biochemical Purification ◽

Heterologous Promoter ◽

Nucleosomal Histone

ABSTRACT Recent studies of histone methylation have yielded fundamental new insights pertaining to the role of this modification in gene activation as well as in gene silencing. While a number of methylation sites are known to occur on histones, only limited information exists regarding the relevant enzymes that mediate these methylation events. We thus sought to identify native histone methyltransferase (HMT) activities from Saccharomyces cerevisiae. Here, we describe the biochemical purification and characterization of Set2, a novel HMT that is site-specific for lysine 36 (Lys36) of the H3 tail. Using an antiserum directed against Lys36 methylation in H3, we show that Set2, via its SET domain, is responsible for methylation at this site in vivo. Tethering of Set2 to a heterologous promoter reveals that Set2 represses transcription, and part of this repression is mediated through the HMT activity of the SET domain. These results suggest that Set2 and methylation at H3 Lys36 play a role in the repression of gene transcription.

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