Non-catalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia

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 non-catalytic function. We reveal that targeting a positively charged cleft of DIMT1, remote from the catalytic site, weakens the binding of DIMT1 to rRNA and mis-localizes DIMT1 to the nucleoplasm, in contrast with the primarily nucleolar localization of wild-type DIMT1. Mechanistically, rRNA binding is required for DIMT1 to undergo liquid-liquid phase separation, which explains why 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 non-catalytic region.