Volume 31, No 6, Jun 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 6, June 2021: 664-683   |  Open Access

ORIGINAL ARTICLES

Mutual dependency between lncRNA LETN and protein NPM1 in controlling the nucleolar structure and functions sustaining cell proliferation

Xianteng Wang^1,2,3 , Xiaolin Hu^1,2,3,4 , Wanlu Song^1,2,3 , Hui Xu^1,2,3 , Zhengtao Xiao^1,2,3 , Rongyao Huang^1,2,3 , Qingran Bai⁵ , Fan Zhang^1,2,3 , Yongzhen Chen^1,2,3 , Yu Liu^1,2,3 , Jianhuo Fang^1,2,3 , Xin Li^1,2,3 , Qin Shen⁵ , Haitao Zhao⁶ , Xuerui Yang^1,2,3,*

¹MOE Key Laboratory of Bioinformatics, Tsinghua University, Beijing 100084, China
²Center for Synthetic & Systems Biology, Tsinghua University, Beijing 100084, China
³School of Life Sciences, Tsinghua University, Beijing 100084, China
⁴Joint Graduate Program of Peking-Tsinghua-National Institute of Biological Science, Beijing 100084, China
⁵Brain and Spinal Cord Innovative Research Center of Tongji Hospital, School of Life Sciences and Technology, Tongji University and Frontier Science Research Center for Stem Cells of Ministry of Education, Shanghai 200092, China
⁶Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing 100730, China
Correspondence: Xuerui Yang(yangxuerui@tsinghua.edu.cn)

Fundamental processes such as ribosomal RNA synthesis and chromatin remodeling take place in the nucleolus, which is hyperactive in fast-proliferating cells. The sophisticated regulatory mechanism underlying the dynamic nucleolar structure and functions is yet to be fully explored. The present study uncovers the mutual functional dependency between a previously uncharacterized human long non-coding RNA, which we renamed LETN, and a key nucleolar protein, NPM1. Specifically, being upregulated in multiple types of cancer, LETN resides in the nucleolus via direct binding with NPM1. LETN plays a critical role in facilitating the formation of NPM1 pentamers, which are essential building blocks of the nucleolar granular component and control the nucleolar functions. Repression of LETN or NPM1 led to similar and profound changes of the nucleolar morphology and arrest of the nucleolar functions, which led to proliferation inhibition of human cancer cells and neural progenitor cells. Interestingly, this inter-dependency between LETN and NPM1 is associated with the evolutionarily new variations of NPM1 and the coincidental emergence of LETN in higher primates. We propose that this human-specific protein–lncRNA axis renders an additional yet critical layer of regulation with high physiological relevance in both cancerous and normal developmental processes that require hyperactive nucleoli.

https://doi.org/10.1038/s41422-020-00458-6

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