Noncatalytic regulation of 18SrRNA methyltransferase DIMT1 in acute myeloid leukemia
Open Access
- 1 April 2023
- journal article
- research article
- Published by Cold Spring Harbor Laboratory in Journal of Bone and Joint Surgery
- Vol. 37 (7-8), 321-335
- https://doi.org/10.1101/gad.350298.122
Abstract
Several rRNA-modifying enzymes install rRNA modifications while participating in ribosome assembly. Here, we show that 18S rRNA methyltransferase DIMT1 is essential for acute myeloid leukemia (AML) proliferation through a noncatalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mislocalizes DIMT1 to the nucleoplasm, in contrast to the primarily nucleolar localization of wild-type DIMT1. Mechanistically, rRNA binding is required for DIMT1 to undergo liquid–liquid phase separation, which explains the distinct nucleoplasm localization of the rRNA binding-deficient DIMT1. Re-expression of wild-type or a catalytically inactive mutant E85A, but not the rRNA binding-deficient DIMT1, supports AML cell proliferation. This study provides a new strategy to target DIMT1-regulated AML proliferation via targeting this essential noncatalytic region.Keywords
Funding Information
- National Institutes of Health (R35 GM133721, R01 HL160726, RSG-22-064-01-RMC)
- American Cancer Research Scholar
- Damon Runyon (Innovator Award, R35 GM118090, R01 CA258904, T32GM07133398)
- Heinrich Kronstein Foundation
This publication has 47 references indexed in Scilit:
- STAR: ultrafast universal RNA-seq alignerBioinformatics, 2012
- Nuclear Ribosome Biogenesis Mediated by the DIM1A rRNA Dimethylase Is Required for Organized Root Growth and Epidermal Patterning in ArabidopsisTHE PLANT CELL ONLINE, 2012
- Structural Insights into Methyltransferase KsgA Function in 30S Ribosomal Subunit Biogenesis*Online Journal of Public Health Informatics, 2012
- Ribosomopathies: human disorders of ribosome dysfunctionBlood, 2010
- Structural Basis for Binding of RNA and Cofactor by a KsgA MethyltransferaseStructure, 2009
- Depletion of nucleophosmin leads to distortion of nucleolar and nuclear structures in HeLa cellsBiochemical Journal, 2008
- Crystal Structure of KsgA, a Universally Conserved rRNA Adenine Dimethyltransferase in Escherichia coliJournal of Molecular Biology, 2004
- Chloroplast Development at Low Temperatures Requires a Homolog of DIM1, a Yeast Gene Encoding the 18S rRNA DimethylaseTHE PLANT CELL ONLINE, 1998
- The DIM1 Gene Responsible for the Conserved m62Am62A Dimethylation in the 3′-Terminal Loop of 18 S rRNA is Essential in YeastJournal of Molecular Biology, 1994
- Characterization of Novikoff hepatoma mRNA methylation and heterogeneity in the methylated 5' terminusBiochemistry, 1975