Journal of Biological Chemistry
Volume 284, Issue 49, 4 December 2009, Pages 34283-34295
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Transcription, Chromatin, and Epigenetics
The Target of the NSD Family of Histone Lysine Methyltransferases Depends on the Nature of the Substrate*

https://doi.org/10.1074/jbc.M109.034462Get rights and content
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The NSD (nuclear receptor SET domain-containing) family of histone lysine methyltransferases is a critical participant in chromatin integrity as evidenced by the number of human diseases associated with the aberrant expression of its family members. Yet, the specific targets of these enzymes are not clear, with marked discrepancies being reported in the literature. We demonstrate that NSD2 can exhibit disparate target preferences based on the nature of the substrate provided. The NSD2 complex purified from human cells and recombinant NSD2 both exhibit specific targeting of histone H3 lysine 36 (H3K36) when provided with nucleosome substrates, but histone H4 lysine 44 is the primary target in the case of octamer substrates, irrespective of the histones being native or recombinant. This disparity is negated when NSD2 is presented with octamer targets in conjunction with short single- or double-stranded DNA. Although the octamers cannot form nucleosomes, the target is nonetheless nucleosome-specific as is the product, dimethylated H3K36. This study clarifies in part the previous discrepancies reported with respect to NSD targets. We propose that DNA acts as an allosteric effector of NSD2 such that H3K36 becomes the preferred target.

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*

This work was supported, in whole or in part, by National Institutes of Health Grants 4R37GM037120–24 (to D. R.), S10 RR017990, P30 NS050276, and P30CA016087 (to T. A. N.) and GM063716 (to R. M. X.). This work was also supported by a grant from the Howard Hughes Medical Institute (to D. R.) and Basic Research Program of China Grant 2009CB825501 (to R. M. X.).

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Present address: Constellation Pharmaceuticals, Sidney St., Cambridge, MA 02139.