SET and MYND domain-containing protein 5 (SMYD5)

SET and MYND domain-containing protein 5 (SMYD5) is a protein-lysine N-methyltransferase and member of the SMYD family of epigenetic regulators, characterized by a split SET domain and a MYND domain[1][3][4]. SMYD5 primarily functions as a ribosomal methyltransferase, specifically trimethylating lysine 22 on the ribosomal protein RPL40, a modification crucial for efficient translation elongation and global protein synthesis[2][3]. SMYD5 also exhibits histone methyltransferase activity, including trimethylation of histone H3 at lysine 36 (H3K36me3) at gene promoters and possibly H4K20, thereby impacting chromatin structure and transcriptional control[4][1]. SMYD5 regulates stem cell differentiation, maintains genome stability via heterochromatin formation, contributes to silencing transposable elements, and represses pro-inflammatory gene expression in macrophages[1]. Clinically, SMYD5 and its RPL40 methylation activity are upregulated in several cancers, notably hepatocellular carcinoma, where they correlate with poor prognosis and contribute to tumorigenesis; targeting SMYD5 may sensitize tumors to mTOR inhibitors, making it a promising but as yet experimental therapeutic target[2][3][4].

Other names

Protein-lysine N-trimethyltransferase SMYD5RAI15RRG1NN8-4AGZMYND23Protein NN8-4AGRetinoic acid-induced protein 15[histone H3]-lysine20 N-trimethyltransferase SMYD5[histone H4]-lysine36 N-trimethyltransferase SMYD5[histone H3]-lysine36 N-trimethyltransferase SMYD5[histone H4]-lysine20 N-trimethyltransferase SMYD5histone-lysine N-trimethyltransferase SMYD5retinoic acid induced 15retinoic acid responsive

Inhibition of SMYD5 disrupts RPL40 lysine methylation, reduces translation output, disrupts elongation, and causes increased ribosome collisions, making cells more sensitive to translation pathway inhibitors (notably mTOR pathway inhibitors)[2][3].