A transfer-RNA-derived small RNA regulates ribosome biogenesis

Hak Kyun Kim; Gabriele Fuchs; Shengchun Wang; Wei Wei; Yue Zhang; Hyesuk Park; Biswajoy Roy-Chaudhuri; Pan Li; Jianpeng Xu; Kirk Chu; Feijie Zhang; Mei-Sze Chua; Samuel So; Qiangfeng Cliff Zhang; Peter Sarnow; Mark A Kay

doi:10.1038/nature25005

A transfer-RNA-derived small RNA regulates ribosome biogenesis

Nature. 2017 Dec 7;552(7683):57-62. doi: 10.1038/nature25005. Epub 2017 Nov 29.

Authors

Hak Kyun Kim^{1

2}, Gabriele Fuchs³, Shengchun Wang^{1

2}, Wei Wei⁴, Yue Zhang^{1

2}, Hyesuk Park^{1

2}, Biswajoy Roy-Chaudhuri^{1

2}, Pan Li⁵, Jianpeng Xu^{1

2}, Kirk Chu^{1

2}, Feijie Zhang^{1

2}, Mei-Sze Chua⁴, Samuel So⁴, Qiangfeng Cliff Zhang⁵, Peter Sarnow³, Mark A Kay^{1

2}

Affiliations

¹ Department of Pediatrics, Stanford University, Stanford, California 94305, USA.
² Department of Genetics, Stanford University, Stanford, California 94305, USA.
³ Department of Microbiology and Immunology, Stanford University, Stanford, California 94305, USA.
⁴ Asian Liver Center, Department of Surgery, Stanford University School of Medicine, Stanford, California 94305, USA.
⁵ MOE Key Laboratory of Bioinformatics, Beijing Advanced Innovation Center for Structural Biology, Center for Synthetic and Systems Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.

Abstract

Transfer-RNA-derived small RNAs (tsRNAs; also called tRNA-derived fragments) are an abundant class of small non-coding RNAs whose biological roles are not well understood. Here we show that inhibition of a specific tsRNA, LeuCAG3'tsRNA, induces apoptosis in rapidly dividing cells in vitro and in a patient-derived orthotopic hepatocellular carcinoma model in mice. This tsRNA binds at least two ribosomal protein mRNAs (RPS28 and RPS15) to enhance their translation. A decrease in translation of RPS28 mRNA blocks pre-18S ribosomal RNA processing, resulting in a reduction in the number of 40S ribosomal subunits. These data establish a post-transcriptional mechanism that can fine-tune gene expression during different physiological states and provide a potential new target for treating cancer.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Apoptosis / genetics
Base Pairing
Base Sequence
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology
Carcinoma, Hepatocellular / therapy
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cell Survival / drug effects
Cell Survival / genetics
Female
HCT116 Cells
HEK293 Cells
HeLa Cells
Humans
Liver Neoplasms / genetics
Liver Neoplasms / pathology
Liver Neoplasms / therapy
Male
Mice
Oligonucleotides, Antisense / genetics
Oligonucleotides, Antisense / pharmacology
Oligonucleotides, Antisense / therapeutic use
Protein Biosynthesis / drug effects
Protein Biosynthesis / genetics
RNA, Messenger / chemistry
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA, Ribosomal, 18S / genetics
RNA, Ribosomal, 18S / metabolism
RNA, Small Untranslated / antagonists & inhibitors
RNA, Small Untranslated / genetics*
RNA, Transfer, Leu / antagonists & inhibitors
RNA, Transfer, Leu / genetics*
Ribosomal Proteins / biosynthesis*
Ribosomal Proteins / genetics
Ribosome Subunits, Small, Eukaryotic / metabolism
Ribosomes / drug effects
Ribosomes / genetics*
Ribosomes / metabolism*
Substrate Specificity / genetics
Xenograft Model Antitumor Assays

Substances

Oligonucleotides, Antisense
RNA, Messenger
RNA, Ribosomal, 18S
RNA, Small Untranslated
RNA, Transfer, Leu
Ribosomal Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding