SET domain-containing protein 3 is a protein-histidine N-methyltransferase that specifically methylates actin at histidine 73. SETD3 was originally identified as a histone lysine methyltransferase, similar to other members of the SET domain-containing enzyme family. However, additional studies have found that SETD3 does not methylate histones, and that it has a much higher affinity for histidine residues compared to lysine. Structural analysis suggests that the SETD3 binding pocket is too shallow to accommodate the aliphatic side chain of lysine, which may partially explain this enzyme’s unique preference for histidine. Methylation of actin at His73 has been suggested to promote F-actin stability and cytoskeletal integrity, although the exact biological function of this modification is not currently known. SETD3 knockout mice are viable, but SETD3-deficient female mice display primary dystocia and have reduced litter sizes, potentially due to defects in smooth muscle contraction. SETD3 also appears to play a role in tumorigenesis, although its exact function is complex. For instance, higher SETD3 expression levels are associated with increased survival rates in breast cancer patients with general subtypes, but increased expression is associated with poor survival in patients with triple-negative and p53 mutant tumors. Knockdown of SETD3 in hepatocellular carcinoma cells has also been shown to reduce proliferation. SETD3 has further been reported to methylate the transcription factor FoxM1, which is overexpressed in a broad range of cancer types and plays an important role in tumorigenesis. Interestingly, a genome-scale CRISPR-Cas9 knockout screen has also revealed that SETD3 is critically important for the pathogenesis of a broad range of enteroviruses. This appears to be due to a novel interaction between the viral 2A protein and the host SETD3 protein, independent of the latter’s methyltransferase activity.
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