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.

中文翻译：

---

急性髓细胞白血病中 18S rRNA 甲基转移酶 DIMT1 的非催化调节

一些 rRNA 修饰酶在参与核糖体组装时安装 rRNA 修饰。在这里，我们证明 18 S rRNA 甲基转移酶 DIMT1 通过非催化功能对于急性髓系白血病 (AML) 增殖至关重要。我们发现，与野生型 DIMT1 主要定位于核仁相比，靶向远离催化位点的 DIMT1 带正电荷的裂口会削弱 DIMT1 与 rRNA 的结合，并使 DIMT1 错误定位到核质。从机制上讲，rRNA 结合是 DIMT1 进行液-液相分离所必需的，这解释了 rRNA 结合缺陷的 DIMT1 的独特核质定位。野生型或催化失活突变体 E85A 的重新表达（而非 rRNA 结合缺陷的 DIMT1）支持 AML 细胞增殖。这项研究提供了一种通过靶向这一重要的非催化区域来靶向 DIMT1 调节的 AML 增殖的新策略。