Autogenous Control of 5′TOP mRNA Stability by 40S Ribosomes

Mol Cell. 2017 Jul 6;67(1):55-70.e4. doi: 10.1016/j.molcel.2017.06.005.

Antonio Gentilella ¹, Francisco D Morón-Duran ², Pedro Fuentes ², Guilherme Zweig-Rocha ², Ferran Riaño-Canalias ², Joffrey Pelletier ², Marta Ruiz ², Gemma Turón ², Julio Castaño ³, Albert Tauler ⁴, Clara Bueno ⁵, Pablo Menéndez ⁶, Sara C Kozma ⁷, George Thomas ⁸

Affiliations

1 Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain; Department of Biochemistry and Physiology, Faculty of Pharmacy, Universitat de Barcelona, 08028 Barcelona, Spain. Electronic address: agentilella@idibell.cat.
2 Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain.
3 Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH 45267-0508, USA.
4 Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain; Department of Biochemistry and Physiology, Faculty of Pharmacy, Universitat de Barcelona, 08028 Barcelona, Spain.
5 Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, 08916 Barcelona, Spain.
6 Josep Carreras Leukemia Research Institute and School of Medicine, University of Barcelona, 08916 Barcelona, Spain; Institut Catala de Recerca i Estudis Avançats (ICREA) Lluis Companys, 08916 Barcelona, Spain.
7 Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain; Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH 45267-0508, USA.
8 Metabolism and Cancer Group, Molecular Mechanisms And Experimental Therapy In Oncology Program, Bellvitge Biomedical Research Institute, IDIBELL, 08908 Barcelona, Spain; Division of Hematology/Oncology, Department of Internal Medicine, University of Cincinnati Medical School, Cincinnati, OH 45267-0508, USA; Physiological Sciences Department, Faculty of Medicine and Health Science, University of Barcelona, 08908 Barcelona, Spain. Electronic address: gthomas@idibell.cat.

PMID: 28673543 DOI: 10.1016/j.molcel.2017.06.005

Abstract

Ribosomal protein (RP) expression in higher eukaryotes is regulated translationally through the 5′TOP sequence. This mechanism evolved to more rapidly produce RPs on demand in different tissues. Here we show that 40S ribosomes, in a complex with the mRNA binding protein LARP1, selectively stabilize 5′TOP mRNAs, with disruption of this complex leading to induction of the impaired ribosome biogenesis checkpoint (IRBC) and p53 stabilization. The importance of this mechanism is underscored in 5q− syndrome, a macrocytic anemia caused by a large monoallelic deletion, which we found to also encompass the LARP1 gene. Critically, depletion of LARP1 alone in human adult CD34+ bone marrow precursor cells leads to a reduction in 5′TOP mRNAs and the induction of p53. These studies identify a 40S ribosome function independent of those in translation that, with LARP1, mediates the autogenous control of 5′TOP mRNA stability, whose disruption is implicated in the pathophysiology of 5q− syndrome.

Keywords

40S ribosomes; 5?TOP mRNAs; 5q(?) syndrome; impaired ribosome biogenesis checkpoint; p53 stabilization; polysome profiles; ribosomal proteins.

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