Many faces of mammalian NSD methyltransferases

Nuclear receptor-binding SET domain (NSD) proteins have been initially described as methyltransferases specific to lysine-36 in histone H3 and associated with active chromatin. However, their role in the regulation of transcription and in overall cellular physiology is much more complex, especially in mammals. The emerging diversity of their targets and, accordingly, the processes in which NSD proteins are involved, shows the importance of their noncanonical functions. A wide functionality apparently requires a complicated control system ensuring proper spatial and temporal activation of NSD methyltransferases. In this review, we discuss the role of NSD proteins in transcription, genome topology, mitosis, oncogenesis, immunity, DSB repair, and known mechanisms regulating their activity. NSD proteins initially described as H3K36-specific methyltransferases methylate a wide range of nonhistone targets. NSD proteins promote gene transcription by affecting RNA polymerase through elongation and transcription factors. NSD1 promotes the spread of DNA methylation, preventing CTCF binding and, as a result, weakening TAD boundaries, while NSD2 strengthens existing TAD boundaries. NSD1–3 affect oncogenesis, inflammation, immune response, and double-stranded breaks response through methylation of nonhistone proteins. NSD proteins participate in the histone code and may also be involved in a universal post-translational modification (PTM) protein code. NSD proteins initially described as H3K36-specific methyltransferases methylate a wide range of nonhistone targets. NSD proteins promote gene transcription by affecting RNA polymerase through elongation and transcription factors. NSD1 promotes the spread of DNA methylation, preventing CTCF binding and, as a result, weakening TAD boundaries, while NSD2 strengthens existing TAD boundaries. NSD1–3 affect oncogenesis, inflammation, immune response, and double-stranded breaks response through methylation of nonhistone proteins. NSD proteins participate in the histone code and may also be involved in a universal post-translational modification (PTM) protein code.