Defining Biological and Biochemical Functions of Noncanonical SET Domain Proteins

• Published in: Journal of molecular biology 2024-04, Vol.436 (7), p.168318-168318, Article 168318
• Main Authors: Sun, Winny, Justice, Isabella, Green, Erin M.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Chromatin; gene regulation; histone modification; Histone-Lysine N-Methyltransferase - metabolism; Lysine - metabolism; methylation; PR-SET Domains; SET domain
• ISSN: 0022-2836; 1089-8638
• DOI: 10.1016/j.jmb.2023.168318

[Display omitted] •A SET domain subfamily contains noncanonical SET domains that lack catalytic activity.•The noncanonical Set3 subfamily proteins perform diverse biological functions.•Defining roles of noncanonical SET domains may yield insights into protein function. Within the SET domain superfamily of lysine methyltransferases, there is a well-conserved subfamily, frequently referred to as the Set3 SET domain subfamily, which contain noncanonical SET domains carrying divergent amino acid sequences. These proteins are implicated in diverse biological processes including stress responses, cell differentiation, and development, and their disruption is linked to diseases including cancer and neurodevelopmental disorders. Interestingly, biochemical and structural analysis indicates that they do not possess catalytic methyltransferase activity. At the molecular level, Set3 SET domain proteins appear to play critical roles in the regulation of gene expression, particularly repression and heterochromatin maintenance, and in some cases, via scaffolding other histone modifying activities at chromatin. Here, we explore the common and unique functions among Set3 SET domain subfamily proteins and analyze what is known about the specific contribution of the conserved SET domain to functional roles of these proteins, as well as propose areas of investigation to improve understanding of this important, noncanonical subfamily of proteins.