A small UTX stabilization domain of Trr is conserved within mammalian MLL3-4/COMPASS and is sufficient to rescue loss of viability in null animals

• Published in: Genes & development 2020-11, Vol.34 (21-22), p.1493-1502
• Main Authors: Rickels, Ryan, Wang, Lu, Iwanaszko, Marta, Ozark, Patrick A, Morgan, Marc A, Piunti, Andrea, Khalatyan, Natalia, Soliman, Shimaa H A, Rendleman, Emily J, Savas, Jeffrey N, Smith, Edwin R, Shilatifard, Ali
• Format: Article
• Language: English
• Subjects: Animals; Conserved Sequence - genetics; DNA-Binding Proteins - genetics; Drosophila melanogaster - genetics; Drosophila Proteins - genetics; Gene Deletion; Gene Expression Regulation - genetics; Genes, Lethal - genetics; HCT116 Cells; Histone-Lysine N-Methyltransferase - genetics; Humans; Oxidoreductases, N-Demethylating - genetics; Protein Domains; Protein Stability; Research Paper
• ISSN: 0890-9369; 1549-5477
• DOI: 10.1101/gad.339762.120

Catalytic-inactivating mutations within the enhancer H3K4 mono-methyltransferase Trr and its mammalian homologs, MLL3/4, cause only minor changes in gene expression compared with whole-gene deletions for these COMPASS members. To identify essential histone methyltransferase-independent functions of Trr, we screened to identify a minimal Trr domain sufficient to rescue Trr-null lethality and demonstrate that this domain binds and stabilizes Utx in vivo. Using the homologous MLL3/MLL4 human sequences, we mapped a short ∼80-amino-acid UTX stabilization domain (USD) that promotes UTX stability in the absence of the rest of MLL3/4. Nuclear UTX stability is enhanced when the USD is fused with the MLL4 HMG-box. Thus, COMPASS-dependent UTX stabilization is an essential noncatalytic function of Trr/MLL3/MLL4, suggesting that stabilizing UTX could be a therapeutic strategy for cancers with MLL3/4 loss-of-function mutations.