Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes.

Autor: Pereboom TC; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Bondt A; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Pallaki P; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Klasson TD; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Goos YJ; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Essers PB; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands., Groot Koerkamp MJ; Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands., Gazda HT; Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA; Harvard Medical School, Boston, MA; Broad Institute, Cambridge, MA., Holstege FC; Molecular Cancer Research, UMC Utrecht, Utrecht, The Netherlands., Costa LD; AP-HP, Service d'Hématologie Biologique, Hôpital Robert Debré, Paris F-75019, France; Université Paris VII-Denis Diderot, Sorbonne Paris Cité, Paris F-75475, France; U773, CRB3, Paris F-75018, France., MacInnes AW; Hubrecht Institute, Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address: a.macinnes@hubrecht.eu.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2014 May; Vol. 42 (5), pp. 394-403.e4. Date of Electronic Publication: 2014 Jan 23.
DOI: 10.1016/j.exphem.2013.12.010
Abstrakt: Diamond-Blackfan anemia (DBA) is a bone marrow failure syndrome linked to mutations in ribosomal protein (RP) genes that result in the impaired proliferation of hematopoietic progenitor cells. The etiology of DBA is not completely understood; however, the ribosomal nature of the genes involved has led to speculation that these mutations may alter the landscape of messenger RNA (mRNA) translation. Here, we performed comparative microarray analysis of polysomal mRNA transcripts isolated from lymphoblastoid cell lines derived from DBA patients carrying various haploinsufficient mutations in either RPS19 or RPL11. Different spectrums of changes were observed depending on the mutant gene, with large differences found in RPS19 cells and very few in RPL11 cells. However, we find that the small number of altered transcripts in RPL11 overlap for the most part with those altered in RPS19 cells. We show specifically that levels of branched-chain aminotransferase-1 (BCAT1) transcripts are significantly decreased on the polysomes of both RPS19 and RPL11 cells and that translation of BCAT1 protein is especially impaired in cells with small RP gene mutations, and we provide evidence that this effect may be due in part to the unusually long 5'UTR of the BCAT1 transcript. The BCAT1 enzyme carries out the final step in the biosynthesis and the first step of degradation of the branched-chain amino acids leucine, isoleucine, and valine. Interestingly, several animal models of DBA have reported that leucine ameliorates the anemia phenotypes generated by RPS19 loss. Our study suggests that RP mutations affect the synthesis of specific proteins involved in regulating amino acid levels that are important for maintaining the normal proliferative capacity of hematopoietic cells.
(Copyright © 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: