Epigenetic transcriptional repression of cellular genes by a viral SET protein.

Viruses recruit host proteins to secure viral genome maintenance and replication. However, whether they modify host histones directly to interfere with chromatin-based transcription is unknown. Here we report that Paramecium bursaria chlorella virus 1 (PBCV-1) encodes a functional SET domain histone Lys methyltransferase (HKMTase) termed vSET, which is linked to rapid inhibition of host transcription after viral infection.

Structural insights of the specificity and catalysis of a viral histone H3 lysine 27 methyltransferase.

SET domain lysine methyltransferases are known to catalyze site and state-specific methylation of lysine residues in histones that is fundamental in epigenetic regulation of gene activation and silencing in eukaryotic organisms. Here we report the three-dimensional solution structure of the SET domain histone lysine methyltransferase (vSET) from Paramecium bursaria chlorella virus 1 bound to cofactor S-adenosyl-L-homocysteine and a histone H3 peptide containing mono-methylated lysine 27. The dimeric structure, mimicking an enzyme/cofactor/substrate complex, yields the structural basis of the substrate specificity and methylation multiplicity of the enzyme.

An archaeal SET domain protein exhibits distinct lysine methyltransferase activity towards DNA-associated protein MC1-alpha.

The evolutionarily conserved SET domain proteins in eukaryotes have been shown to function as site-specific histone lysine methyltransferases, and play an important role in regulating chromatin-mediated gene transcriptional activation and silencing. Structure-based sequence analysis has revealed that SET domains are also encoded by viruses and bacteria, as well as Archaea. However, their cellular functions remain elusive.

A dimeric viral SET domain methyltransferase specific to Lys27 of histone H3.

Site-specific lysine methylation of histones by SET domains is a hallmark for epigenetic control of gene transcription in eukaryotic organisms. Here we report that a SET domain protein from Paramecium bursaria chlorella virus can specifically di-methylate Lys27 in histone H3, a modification implicated in gene silencing. The solution structure of the viral SET domain reveals a butterfly-shaped head-to-head symmetric dimer different from other known protein methyltransferases.