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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
Genes & development, 11/2020, Letnik: 34, Številka: 21-22Journal Article
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.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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