Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes
Translation of branched-chain aminotransferase-1 transcripts is impaired in cells haploinsufficient for ribosomal protein genes
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DOI：
10.1016/j.exphem.2013.12.010
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发表时间：
2014-05-01
影响因子：
2.6
通讯作者：
MacInnes, Alyson W.
中科院分区：
文献类型：
--
作者：
Pereboom, Tamara C.;Bondt, Albert;MacInnes, Alyson W.
Diamond-Blackfan贫血（DBA）是一种与核糖体蛋白（RP）基因突变相关的骨髓衰竭综合征，导致造血祖细胞增殖受损。DBA的病因还不完全清楚;然而，所涉及的基因的核糖体性质已经导致推测这些突变可能改变信使RNA（mRNA）翻译的景观。在这里，我们进行了比较微阵列分析的多核糖体mRNA转录物分离的淋巴母细胞样细胞系来自DBA患者携带各种单倍不足的突变，无论是RPS 19或RPL 11。根据突变基因的不同，观察到不同的变化谱，在RPS 19细胞中发现了很大的差异，而在RPL 11细胞中发现了很少的差异。然而，我们发现RPL 11中少量改变的转录物与RPS 19细胞中改变的转录物大部分重叠。我们特别表明，支链氨基转移酶-1（BCAT 1）转录水平显着降低的多核糖体的RPS 19和RPL 11细胞和BCAT 1蛋白的翻译是特别受损的小RP基因突变的细胞，我们提供的证据表明，这种影响可能部分是由于异常长的5 'UTR的BCATI转录。BCAT 1酶进行生物合成的最后一步和支链氨基酸亮氨酸、异亮氨酸和缬氨酸降解的第一步。有趣的是，DBA的几种动物模型已经报道亮氨酸改善由RPS 19损失产生的贫血表型。我们的研究表明，RP突变影响参与调节氨基酸水平的特定蛋白质的合成，这些氨基酸水平对维持造血细胞的正常增殖能力很重要。(C)2014 ISEH -血液学和干细胞学会。爱思唯尔公司出版
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 BCATI 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. (C) 2014 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.