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

Abstract

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.

Iron–sulfur clusters as inhibitors and catalysts of viral replication

“…Thus, acetylation of histones H3 and H4 by Elp3 of the elongator complex 47,48 could prime the innate immune response recruiting RNA Pol-II. Consistently, the Elp3 subunit of the elongator complex plays a vital role in epigenetics and regulation of the immune response 68 , and in Drosophila melanogaster 69 , plants 70 and humans 71,72 , Elp3 positively regulates the innate immune response. Additionally, in the cytoplasm the radical-SAM activity of Elp3 should play a role in priming innate and trained immunity.…”

Elp3‐mediated codon‐dependent translation promotes mTORC2 activation and regulates macrophage polarization

“…Elp3 deficiency in T cells or in the hematopoietic system causes Atf4 stabilization (Lemaitre et al , 2021 ; Rosu et al , 2021 ). Although stabilized ATF4 promotes rather than inhibit M2 macrophage polarization (Kim et al , 2018 ), we nevertheless addressed ATF4 expression in peritoneal macrophages lacking Elp3 expression.…”

“…The loss of Elp3 in cortical progenitors, T cells as well as in the hematopoietic system causes Atf4 stabilization, which largely underlies the phenotypical defects in mice (Laguesse et al , 2015 ; Lemaitre et al , 2021 ; Rosu et al , 2021 ). We have not seen any robust Atf4 stabilization in peritoneal macrophages lacking Elp3 expression, suggesting that Atf4 stabilization is not a systematic consequence of Elp3 deficiency in primary cells.…”

“…Lack of Elp3 in peritoneal macrophages does not stabilize Atf4Elp3 deficiency in T cells or in the hematopoietic system causes Atf4 stabilization(Lemaitre et al, 2021;Rosu et al, 2021). Although…”

tRNA Function and Dysregulation in Cancer

“…Conversely, a decrease in wobble uridine modifications was demonstrated to be detrimental in hematopoiesis. In a mouse model, an inactivation of Elp3, the catalytic subunit of the elongator that modifies wobble uridine in tRNAs, led to p53 mutation-driven leukemia/lymphoma ( Rosu et al, 2021 ). These functions of tRNA modification are further complicated by debate over whether these tRNA modifications directly impact the expression of stress-related proteins or act in stress signaling ( Kirchner & Ignatova, 2014 ).…”