Abstract
NSD3 is one of six H3K36-specific lysine methyltransferases in metazoans, and the methylation of H3K36 is associated with active transcription. NSD3 is a member of the nuclear receptor-binding SET domain (NSD) family of histone methyltransferases together with NSD1 and NSD2, which generate mono- and dimethylated lysine on histone H3. NSD3 is mutated and hyperactive in some human cancers, but the biochemical mechanisms underlying such dysregulation are barely understood. In this review, the current knowledge of NSD3 is systematically reviewed. Finally, the molecular and functional characteristics of NSD3 in different tumor types according to the current research are summarized.
Highlights
Domain (PHD5) and the adjacent Cys-His-rich domain (C5HCH), located at the C terminus of NSD3, fold into a novel plant homeo domains (PHD)-PHD-like module recognizing the unmodified H3K4 and trimethylated H3K9 by PHD5. This function is not conserved between members of the nuclear receptorbinding SET domain (NSD) family, with PHD5 of NSD2 showing stronger preference for unmethylated H3K9 (H3K9me0) than trimethylated H3K9 (H3K9me3), and the NSD1 PHD5-C5HCH showed no binding to histone peptides at all [18], but is in involved in binding to the transcription cofactor Nizp1 in NSD1 [19,20,21]
Apart from histone substrates, NSD3 recently was reported to methylate the epidermal growth factor receptor (EGFR), leading to enhanced activation [64], and NSD1 was shown to mono- and dimethylate p65, an NF-κB family transcription factor, at K218 and K221, which stimulates the expression of p65-dependent tumorigenic genes [65]
E1181K and T1232A substitution leads to enhanced enzymatic activity through preventing the autoinhibitory loop from blocking the active site, which improves the insertion of the target H3K36 into the catalytic pocket of NSD3 [35,79]
Summary
In order to establish or maintain a cell-type-specific gene expression program, the chromatin structures need to be highly dynamic to allow access of transcription factors and other regulatory entities to the DNA at defined time points. These events are tightly regulated by post-translational modifications (PTMs) which are enriched at the unstructured and flexible N-terminal regions of the histone proteins. These histone tails protrude from the nucleosome core and are subject to a diverse array of PTMs, e.g., acetylation, phosphorylation, ubiquitination and methylation, often referred to as the “histone code”. The structural and functional features of NSD3 will be discussed in more detail with references to the other family members in case information is available
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