Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis.

The Journal of experimental medicine 2021 Mar 01

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The hematopoietic system is highly sensitive to perturbations in the translational machinery, of which an emerging level of regulation lies in the epitranscriptomic modification of transfer RNAs (tRNAs). Here, we interrogate the role of tRNA anticodon modifications in hematopoiesis by using mouse models of conditional inactivation of Elp3, the catalytic subunit of Elongator that modifies wobble uridine in specific tRNAs. Loss of Elp3 causes bone marrow failure by inducing death in committing progenitors and compromises the grafting activity of hematopoietic stem cells. Mechanistically, Elp3 deficiency activates a p53-dependent checkpoint in what resembles a misguided amino acid deprivation response that is accompanied by Atf4 overactivation and increased protein synthesis. While deletion of p53 rescues hematopoiesis, loss of Elp3 prompts the development of p53-mutated leukemia/lymphoma, and inactivation of p53 and Elongator cooperatively promotes tumorigenesis. Specific tRNA-modifying enzymes thus condition differentiation and antitumor fate decisions in hematopoietic stem cells and progenitors. © 2021 Rosu et al.

Citation

Adeline Rosu, Najla El Hachem, Francesca Rapino, Kevin Rouault-Pierre, Joseph Jorssen, Joan Somja, Eve Ramery, Marc Thiry, Laurent Nguyen, Maarten Jacquemyn, Dirk Daelemans, Christopher M Adams, Dominique Bonnet, Alain Chariot, Pierre Close, Fabrice Bureau, Christophe J Desmet. Loss of tRNA-modifying enzyme Elp3 activates a p53-dependent antitumor checkpoint in hematopoiesis. The Journal of experimental medicine. 2021 Mar 01;218(3)