Matches in SemOpenAlex for { <https://semopenalex.org/work/W3110702022> ?p ?o ?g. }
- W3110702022 abstract "Summary Dimethylated histone H3 Lys36 (H3K36me2) regulates gene expression by antagonizing the repressive effect of polycomb-group proteins. Aberrant upregulation of H3K36me2, either by overexpression or point mutations of NSD2/MMSET, an H3K36 dimethyltransferase, is found in various cancers, including multiple myeloma. To understand the mechanism underlying its regulation, here we report the cryo-electron microscopy structure of the catalytic fragment of NSD2 bound to the nucleosome at 2.8 Å resolution. The nucleosomal DNA is partially unwrapped at superhelix location +5.5, facilitating the access of NSD2 to H3K36. NSD2 interacts with DNA and H2A along with H3. The autoinhibitory loop of NSD2 changes its conformation upon nucleosome binding to accommodate H3 in its substrate-binding cleft. Kinetic analysis revealed two oncogenic mutations, E1099K and T1150A, to aberrantly activate NSD2 by increasing its catalytic turnover but not the nucleosome affinity. 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 the catalytic turnover. Our analyses would guide the development of specific inhibitors of NSD2 for the treatment of various cancers." @default.
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- W3110702022 date "2020-12-06" @default.
- W3110702022 modified "2023-10-03" @default.
- W3110702022 title "Structural basis of the regulation of normal and oncogenic methylation of nucleosomal histone H3 Lys36 by NSD2" @default.
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- W3110702022 doi "https://doi.org/10.1101/2020.12.05.413278" @default.
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