Structural basis of the regulation of the normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2

Ko Sato, Amarjeet Kumar, Keisuke Hamada, Chikako Okada, Asako Oguni, Ayumi Machiyama, Shun Sakuraba, Tomohiro Nishizawa, Osamu Nureki, Hidetoshi Kono, Kazuhiro Ogata () and Toru Sengoku ()
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Ko Sato: Yokohama City University Graduate School of Medicine
Amarjeet Kumar: National Institutes for Quantum Science and Technology
Keisuke Hamada: Yokohama City University Graduate School of Medicine
Chikako Okada: Yokohama City University Graduate School of Medicine
Asako Oguni: Yokohama City University Graduate School of Medicine
Ayumi Machiyama: Yokohama City University Graduate School of Medicine
Shun Sakuraba: National Institutes for Quantum Science and Technology
Tomohiro Nishizawa: Graduate School of Science, The University of Tokyo
Osamu Nureki: Graduate School of Science, The University of Tokyo
Hidetoshi Kono: National Institutes for Quantum Science and Technology
Kazuhiro Ogata: Yokohama City University Graduate School of Medicine
Toru Sengoku: Yokohama City University Graduate School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-10

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26913-5

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