A novel route to product specificity in the Suv4-20 family of histone H4K20 methyltransferases

The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencin...

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Published in:Nucleic acids research Vol. 42; no. 1; pp. 661 - 671
Main Authors: Southall, Stacey M., Cronin, Nora B., Wilson, Jon R.
Format: Journal Article
Language:English
Published: England Oxford University Press 01.01.2014
Subjects:
Amino Acid Sequence
Animals
Catalytic Domain
Drosophila Proteins - chemistry
Drosophila Proteins - metabolism
Histone-Lysine N-Methyltransferase - chemistry
Histone-Lysine N-Methyltransferase - classification
Histone-Lysine N-Methyltransferase - metabolism
Histones - chemistry
Histones - metabolism
Mice
Models, Molecular
Molecular Sequence Data
S-Adenosylmethionine - chemistry
S-Adenosylmethionine - metabolism
Structural Biology
Substrate Specificity
ISSN:0305-1048, 1362-4962, 1362-4962
Online Access:Get full text
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Summary:The delivery of site-specific post-translational modifications to histones generates an epigenetic regulatory network that directs fundamental DNA-mediated processes and governs key stages in development. Methylation of histone H4 lysine-20 has been implicated in DNA repair, transcriptional silencing, genomic stability and regulation of replication. We present the structure of the histone H4K20 methyltransferase Suv4-20h2 in complex with its histone H4 peptide substrate and S-adenosyl methionine cofactor. Analysis of the structure reveals that the Suv4-20h2 active site diverges from the canonical SET domain configuration and generates a high degree of both substrate and product specificity. Together with supporting biochemical data comparing Suv4-20h1 and Suv4-20h2, we demonstrate that the Suv4-20 family enzymes take a previously mono-methylated H4K20 substrate and generate an exclusively di-methylated product. We therefore predict that other enzymes are responsible for the tri-methylation of histone H4K20 that marks silenced heterochromatin.
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Present addresses: Jon R. Wilson, Division of Molecular Structure, National Institute for Medical Research, Mill Hill, London NW7 1AA, UK. Stacey M. Southall, EMBL Hamburg, Notkestraße 85, 22603 Hamburg, Germany.
ISSN:0305-1048
1362-4962
1362-4962
DOI:10.1093/nar/gkt776