Autogenous Control of 5 ' TOP mRNA Stability by 40S Ribosomes
Por:
Gentilella, A, Moron-Duran, FD, Fuentes, P, Zweig-Rocha, G, Riano-Canalias, F, Pelletier, J, Ruiz, M, Turon, G, Castano, J, Tauler, A, Bueno, C, Menendez, P, Kozma, SC and Thomas, G
Publicada:
6 jul 2017
Resumen:
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.
Filiaciones:
Gentilella, A:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Univ Barcelona, Fac Pharm, Dept Biochem & Physiol, E-08028 Barcelona, Spain
Moron-Duran, FD:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Fuentes, P:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Univ Autonoma Barcelona, Dept Surg & Morphol Sci, Vail dHebron Inst Recerca, Barcelona 08035, Spain
Zweig-Rocha, G:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Riano-Canalias, F:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Pelletier, J:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Ruiz, M:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Turon, G:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Inst Res Biomed, Baldiri Reixac 10, Barcelona 08028, Spain
Castano, J:
Univ Cincinnati, Sch Med, Dept Internal Med, Div Hematol Oncol, Cincinnati, OH 45267 USA
Tauler, A:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Univ Barcelona, Fac Pharm, Dept Biochem & Physiol, E-08028 Barcelona, Spain
:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Barcelona 08916, Spain
Univ Barcelona, Sch Med, Barcelona 08916, Spain
:
Univ Barcelona, Josep Carreras Leukemia Res Inst, Barcelona 08916, Spain
Univ Barcelona, Sch Med, Barcelona 08916, Spain
Inst Catala Recerca & Estudis Avangats ICREA Llui, Barcelona 08916, Spain
Kozma, SC:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Univ Cincinnati, Sch Med, Dept Internal Med, Div Hematol Oncol, Cincinnati, OH 45267 USA
Thomas, G:
IDIBELL, Bellvitge Biomed Res Inst, Mol Mech & Expt Therapy Oncol Program, Metab & Canc Grp, Barcelona 08908, Spain
Univ Cincinnati, Sch Med, Dept Internal Med, Div Hematol Oncol, Cincinnati, OH 45267 USA
Univ Barcelona, Fac Med & Hlth Sci, Physiol Sci Dept, Barcelona 08908, Spain
Bronze, Green Accepted
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