Abstract
Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression, and aberrant H3K36me2 upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Here we report the cryo-electron microscopy structure of NSD2 bound to the nucleosome. Nucleosomal DNA is partially unwrapped, facilitating NSD2 access to H3K36. NSD2 interacts with DNA and H2A along with H3. The NSD2 autoinhibitory loop changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed that two oncogenic mutations, E1099K and T1150A, increase NSD2 catalytic turnover. Molecular dynamics simulations suggested that in both mutants, the autoinhibitory loop adopts an open state that can accommodate H3 more often than the wild-type. We propose that E1099K and T1150A destabilize the interactions that keep the autoinhibitory loop closed, thereby enhancing catalytic turnover. Our analyses guide the development of specific inhibitors of NSD2.
Highlights
Dimethylated histone H3 Lys[36] (H3K36me2) regulates gene expression, and aberrant H3K36me[2] upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers
We solved a 2.8-Å resolution cryo-electron microscopy structure of the complex formed by the catalytic fragment of human NSD2 bearing an E1099K mutation and a nucleosome in the presence of sinefungin, an analog of S-adenosyl methionine (SAM) (Supplementary Figs. 1, 2, Supplementary Table 1)
Our structural and kinetic analyses show that the oncogenic E1099K and T1150A mutants increase the catalytic turnover of NSD2, leading to its hyperactivation
Summary
Dimethylated histone H3 Lys[36] (H3K36me2) regulates gene expression, and aberrant H3K36me[2] upregulation, resulting from either the overexpression or point mutation of the dimethyltransferase NSD2, is found in various cancers. Aberrant upregulation of cellular H3K36me[2] levels, induced by the overexpression or point mutation of NSD2, has been found in various cancers. A recurrent point mutation in the catalytic SET domain, NSD2 p.E1099K, has been found in patients with acute lymphoblastic leukemia[10] and other types of cancers[11] and is known to aberrantly activate H3K36 methyltransferase activity[10,11]. Another recurrent mutation in the SET domain, NSD2 p.T1150A, has been found in mantle cell lymphoma along with the p.E1099K mutation[12] and was recently shown to be catalytically hyperactivated[13]
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