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人类DUS1L催化tRNA第16/17位的二氢尿嘧啶修饰，且DUS1L的过表达会干扰翻译。

Human DUS1L catalyzes dihydrouridine modification at tRNA positions 16/17, and DUS1L overexpression perturbs translation.

作者信息

Matsuura Jin, Akichika Shinichiro, Wei Fan-Yan, Suzuki Tsutomu, Yamamoto Takahiro, Watanabe Yuka, Valášek Leoš Shivaya, Mukasa Akitake, Tomizawa Kazuhito, Chujo Takeshi

机构信息

Department of Molecular Physiology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

Department of Neurosurgery, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.

出版信息

Commun Biol. 2024 Oct 2;7(1):1238. doi: 10.1038/s42003-024-06942-8.

DOI:10.1038/s42003-024-06942-8
PMID:39354220
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11445529/
Abstract

Human cytoplasmic tRNAs contain dihydrouridine modifications at positions 16 and 17 (D16/D17). The enzyme responsible for D16/D17 formation and its cellular roles remain elusive. Here, we identify DUS1L as the human tRNA D16/D17 writer. DUS1L knockout in the glioblastoma cell lines LNZ308 and U87 causes loss of D16/D17. D formation is reconstituted in vitro using recombinant DUS1L in the presence of NADPH or NADH. DUS1L knockout/overexpression in LNZ308 cells shows that DUS1L supports cell growth. Moreover, higher DUS1L expression in glioma patients is associated with poorer prognosis. Upon vector-mediated DUS1L overexpression in LNZ308 cells, 5' and 3' processing of precursor tRNA is inhibited, resulting in a reduced mature tRNA level, reduced translation of the tyrosine codons UAC and UAU, and reduced translational readthrough of the near-cognate stop codons UAA and UAG. Moreover, DUS1L overexpression increases the amounts of several D16/D17-containing tRNAs and total cellular translation. Our study identifies a human dihydrouridine writer, providing the foundation to study its roles in health and disease.

摘要

人类细胞质转运RNA（tRNA）在第16和17位含有二氢尿苷修饰（D16/D17）。负责D16/D17形成的酶及其细胞作用仍不清楚。在这里，我们鉴定出DUS1L是人tRNA D16/D17的写入酶。胶质母细胞瘤细胞系LNZ308和U87中的DUS1L基因敲除导致D16/D17缺失。在存在烟酰胺腺嘌呤二核苷酸磷酸（NADPH）或烟酰胺腺嘌呤二核苷酸（NADH）的情况下，使用重组DUS1L在体外重建了D的形成。LNZ308细胞中的DUS1L基因敲除/过表达表明DUS1L支持细胞生长。此外，胶质瘤患者中较高的DUS1L表达与较差的预后相关。在LNZ308细胞中通过载体介导DUS1L过表达后，前体tRNA的5'和3'加工受到抑制，导致成熟tRNA水平降低，酪氨酸密码子UAC和UAU的翻译减少，以及近同源终止密码子UAA和UAG的翻译通读减少。此外，DUS1L过表达增加了几种含有D16/D17的tRNA的量和总细胞翻译。我们的研究鉴定出一种人类二氢尿苷写入酶，为研究其在健康和疾病中的作用奠定了基础。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/5fda23ce2ab5/42003_2024_6942_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/9258c4cb1547/42003_2024_6942_Fig1_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/c5a6b1e785fd/42003_2024_6942_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/80393ff00439/42003_2024_6942_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/fbc542fcc7e9/42003_2024_6942_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/5fda23ce2ab5/42003_2024_6942_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/9258c4cb1547/42003_2024_6942_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/13413baba285/42003_2024_6942_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/ef7f6c683392/42003_2024_6942_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/c5a6b1e785fd/42003_2024_6942_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/80393ff00439/42003_2024_6942_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/fbc542fcc7e9/42003_2024_6942_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/edae/11445529/5fda23ce2ab5/42003_2024_6942_Fig7_HTML.jpg

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