Mutual dependency between lncRNA LETN and protein NPM1 in controlling the nucleolar structure and functions sustaining cell proliferation
Open Access
- 11 January 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Research
- Vol. 31 (6), 664-683
- https://doi.org/10.1038/s41422-020-00458-6
Abstract
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.Keywords
Funding Information
- Ministry of Science and Technology of the People’s Republic of China (2016YFC0906001)
- Tsinghua University (2020Z99CFZ022)
- National Natural Science Foundation of China (81972912, 31671381, 91540109)
This publication has 88 references indexed in Scilit:
- CPAT: Coding-Potential Assessment Tool using an alignment-free logistic regression modelNucleic Acids Research, 2013
- Nucleophosmin mutations alter its nucleolar localization by impairing G-quadruplex binding at ribosomal DNANucleic Acids Research, 2013
- Understanding transcriptional regulation by integrative analysis of transcription factor binding dataGenome Research, 2012
- The GENCODE v7 catalog of human long noncoding RNAs: Analysis of their gene structure, evolution, and expressionGenome Research, 2012
- Landscape of transcription in human cellsNature, 2012
- Function of homo- and hetero-oligomers of human nucleoplasmin/nucleophosmin family proteins NPM1, NPM2 and NPM3 during sperm chromatin remodelingNucleic Acids Research, 2012
- Normal Development of Brain CircuitsNeuropsychopharmacology, 2009
- Genome-wide identification of post-translational modulators of transcription factor activity in human B cellsNature Biotechnology, 2009
- Nucleolus: the fascinating nuclear bodyHistochemistry and Cell Biology, 2007
- Global functional analysis of nucleophosmin in Taxol response, cancer, chromatin regulation, and ribosomal DNA transcriptionExperimental Cell Research, 2007