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Loss of transfer RNA U34 modifying enzymes impairs hematopoietic stem and progenitor cell differentiation and function
Rosu, Adeline; Bai, Qiang; Ramery, Eve et al.
2017Keystone Symposia: Hematopoiesis
 

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Keywords :
stem cell; differentiation; translation
Abstract :
[en] Hematopoietic stem and progenitor cells (HSPCs) require fine-tuned protein translation for their normal maintenance and function. Conserved modifications of the wobble uridine base (U34) in transfer RNAs catalyzed by the Elongator complex are required for optimal protein translation efficacy and fidelity, but their biological importance in mammalian stem and progenitor cells remains largely unexplored. Here, we studied the impact of loss of activity of the catalytic subunit Elp3 of Elongator on HSPC differentiation and function. Hematopoietic-cell-specific depletion of Elp3 in conditional knockout mice resulted in shortened lifespan associated with hematopoietic failure and lymphoma development. Elp3 deletion caused apoptosis of specific bone marrow multipotent progenitors and blocked differentiation of committed progenitors, resulting in blood and bone marrow pancytopenia. In contrast, Elp3-deficient hematopoietic stem cells (HSCs) expanded with age and did not exhaust throughout life, although they were defective in reconstituting hematopoiesis in competitive transplantation assays. Mechanistically, loss of Elp3 did not result in detectable alterations in global protein synthesis rates in any HSPC subset. Rather, Elp3-deficient HSPCs displayed enhanced activity of the stress integrator and apoptosis and cell cycle regulator p53. Thus, this study supports the notion that Elongator activity is required in distinct HSPC subsets to avoid aberrant p53 activation, which otherwise results in discrete loss of function phenotypes in HSCs and downstream progenitors.
Disciplines :
Anatomy (cytology, histology, embryology...) & physiology
Author, co-author :
Rosu, Adeline ;  Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Bai, Qiang  ;  Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Ramery, Eve ;  Université de Liège > Dép. clinique des animaux de compagnie et des équidés (DCA) > Biochimie médicale
Thiry, Marc  ;  Université de Liège > Département des sciences de la vie > GIGA-R : Biologie cellulaire
Close, Pierre  ;  Université de Liège > Département de pharmacie > Chimie médicale
Bureau, Fabrice ;  Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Desmet, Christophe  ;  Université de Liège > Département des sciences fonctionnelles (DSF) > GIGA-R : Biochimie et biologie moléculaire
Language :
English
Title :
Loss of transfer RNA U34 modifying enzymes impairs hematopoietic stem and progenitor cell differentiation and function
Publication date :
03 February 2017
Event name :
Keystone Symposia: Hematopoiesis
Event place :
Banff, Canada
Event date :
du 31 janvier au 4 février 2017
By request :
Yes
Audience :
International
Available on ORBi :
since 02 June 2017

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