Journal
JOURNAL OF BIOMOLECULAR SCREENING
Volume 19, Issue 6, Pages 928-935Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1087057114525854
Keywords
WHSC1; WHSC1L1; MMSET; Sotos syndrome; cancer; histone methyltransferase
Funding
- AbbVie
- Boehringer Ingelheim
- Canada Foundation for Innovation
- Canadian Institutes for Health Research
- Genome Canada through the Ontario Genomics Institute [OGI-055]
- GlaxoSmithKline
- Janssen
- Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Research and Innovation
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/]
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The nuclear receptor SET domain-containing family of proteins (NSD1, NSD2, and NSD3) is known to mono-and dimethylate lysine 36 of histone H3 (H3K36). Overexpression and translocation of NSDs have been widely implicated in a variety of diseases including cancers. Although the substrate specificity of NSDs has been a subject of many valuable studies, the activity of these proteins has never been fully characterized in vitro. In this study, we present full kinetic characterization of NSD1, NSD2, and NSD3 and provide robust in vitro assays suitable for screening these proteins in a 384-well format using nucleosome as a substrate. Through monitoring the changes in substrate specificity of a series of NSD constructs and using molecular modeling, we show that a basic post-SET extension common to all three NSDs (corresponding to residues 1209 to 1226 of NSD2) is essential for proper positioning on nucleosome substrates.
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