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缬氨酸tRNA水平和可用性调节白血病中复合物I的组装
2021-12-26 14:28
来源：小柯机器人

美国纽约大学Iannis Aifantis、Palaniraja Thandapani等研究人员合作发现，缬氨酸tRNA水平和可用性调节白血病中复合物I的组装。相关论文于2021年12月22日在线发表在《自然》杂志上。

研究人员使用CRISPR-Cas9筛选，关注了与转运RNA（tRNA）生物生成有关的基因，并确定了缬氨酸tRNA生物生成的改变增强T细胞急性淋巴细胞白血病（T-ALL）中线粒体生物能的机制。缬氨酸氨酰tRNA合成酶的表达被NOTCH1转录上调，NOTCH1是T-ALL的一个关键肿瘤基因，这强调了肿瘤转录程序在协调tRNA供需方面的作用。通过限制饮食中缬氨酸的摄入量来限制缬氨酸的生物利用度，破坏了小鼠的这种平衡，导致白血病负担减少，体内生存率增加。
 
从机制上讲，缬氨酸限制降低了编码线粒体复合体I亚单位的mRNA翻译率，导致复合体I的组装缺陷和氧化磷酸化受损。最后，在不同的缬氨酸条件下进行的全基因组CRISPR-Cas9功能缺失筛选确定了几个基因，包括SLC7A5和BCL2，其基因消减或药物抑制与缬氨酸限制协同作用，减少T-ALL生长。这些研究结果表明，tRNA失调是T-ALL发病机制中的一个关键适应因素，并为在血液恶性肿瘤中使用饮食方法来靶向tRNA生物生成提供了分子基础。
 
据悉，尽管tRNA生物生成的失调促进了癌症中促肿瘤发生的mRNA的翻译，但对肿瘤发生中tRNA失调的机制和后果还不甚了解。
 
附：英文原文
 
Title: Valine tRNA levels and availability regulate complex I assembly in leukaemia

Author: Thandapani, Palaniraja, Kloetgen, Andreas, Witkowski, Matthew T., Glytsou, Christina, Lee, Anna K., Wang, Eric, Wang, Jingjing, LeBoeuf, Sarah E., Avrampou, Kleopatra, Papagiannakopoulos, Thales, Tsirigos, Aristotelis, Aifantis, Iannis

Issue&Volume: 2021-12-22

Abstract: Although deregulation of transfer RNA (tRNA) biogenesis promotes the translation of pro-tumorigenic mRNAs in cancers1,2, the mechanisms and consequences of tRNA deregulation in tumorigenesis are poorly understood. Here we use a CRISPR–Cas9 screen to focus on genes that have been implicated in tRNA biogenesis, and identify a mechanism by which altered valine tRNA biogenesis enhances mitochondrial bioenergetics in T cell acute lymphoblastic leukaemia (T-ALL). Expression of valine aminoacyl tRNA synthetase is transcriptionally upregulated by NOTCH1, a key oncogene in T-ALL, underlining a role for oncogenic transcriptional programs in coordinating tRNA supply and demand. Limiting valine bioavailability through restriction of dietary valine intake disrupted this balance in mice, resulting in decreased leukaemic burden and increased survival in vivo. Mechanistically, valine restriction reduced translation rates of mRNAs that encode subunits of mitochondrial complex I, leading to defective assembly of complex I and impaired oxidative phosphorylation. Finally, a genome-wide CRISPR–Cas9 loss-of-function screen in differential valine conditions identified several genes, including SLC7A5 and BCL2, whose genetic ablation or pharmacological inhibition synergized with valine restriction to reduce T-ALL growth. Our findings identify tRNA deregulation as a critical adaptation in the pathogenesis of T-ALL and provide a molecular basis for the use of dietary approaches to target tRNA biogenesis in blood malignancies.

DOI: 10.1038/s41586-021-04244-1

Source: https://www.nature.com/articles/s41586-021-04244-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html


本期文章：《自然》：Online/在线发表

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