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bioRxiv · 10.1101/2023.03.18.533235

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

Gonskikh, Y.·Stoute, J.·Shen, H.·Pingul, B.·Budinich, K.·Schultz, K.·Elashal, H.·Marmorstein, R. F.·Shi, J.·Liu, K. F.
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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.

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Gonskikh, Y., Stoute, J., Shen, H., Pingul, B., Budinich, K., Schultz, K., Elashal, H., Marmorstein, R. F., Shi, J., Liu, K. F.. 2023-03-19. Non-catalytic regulation of 18S rRNA methyltransferase DIMT1 in acute myeloid leukemia. https://doi.org/10.1101/2023.03.18.533235

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