Disrupting tRNA modifications to target mitochondrial vulnerabilities in drug-resistant leukemia cells.

ABSTRACT:

Abstract

Dysregulated RNA modifications contribute to cancer progression and therapy resistance, yet the underlying mechanism often remains unknown. Here, we perform CRISPR-based synthetic lethality screens to systematically explore the role of RNA modifications in mediating resistance to antileukemic drugs. We identify the tRNA methyltransferase 5 (TRMT5)-mediated formation of N1-methylguanosine (m1G) in the transfer RNA (tRNA) anticodon loop as essential for mediating drug tolerance to cytarabine and venetoclax (Ven) in acute myeloid leukemia (AML). TRMT5 methylates nearly all mitochondrial and nuclear tRNAs with a guanosine at position 37, but its role in promoting drug tolerance specifically depends on its mitochondrial function. TRMT5 is essential for the dynamic upregulation

SUBMITTER: Pauli C 

PROVIDER: S-EPMC12824680 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature