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Elucidating structure–function relationships in the mammalian nucleolus

Nature Reviews Molecular Cell Biology (2026) Cite this article

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Abstract

The nucleolus is the site of ribosomal RNA synthesis and ribosome biogenesis. Advances in high-resolution imaging and next-generation sequencing have unveiled unprecedented details of its intricate architecture and dynamic organization. In this Review, we focus on the dynamic organization of mammalian nucleoli, while drawing selective comparisons with other organisms to highlight conserved and divergent principles of nucleolar organization. We discuss recent progress in deciphering the multilayered compartments of nucleoli, the physical principles driving their organization and dynamics, and their functional interplay during stepwise ribosomal RNA processing, ribosome assembly and maintenance of compartment integrity. We also discuss how disruptions of nucleolar structure–function relationships can drive cellular stresses and diseases, offering new opportunities for therapeutic interventions.

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Fig. 1: Compartmentalized organization and functions of the nucleolus.
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Fig. 2: Nucleolus assembly factors and snoRNPs coordinate ribosome assembly during transcription.
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Fig. 3: LncRNAs as regulators of nucleolar architecture and function.
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Fig. 4: Physical principles governing nucleolar organization.
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Fig. 5: Nucleolar compartment-specific dysfunctions.
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Acknowledgements

The authors thank Y.-H. Pan and M.-L. Hou for critical reading of our manuscript. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB0570000) and the National Key R&D Program of China (no. 2021YFA1100203). This work has been supported by the New Cornerstone Science Foundation through the New Cornerstone Investigator Program and the Ruisi Research Center for Life Science, Minhang District, Shanghai. L.-L.C. is also a Shanghai Academy of Natural Sciences Senior Investigator.

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Authors and Affiliations

  1. State Key Laboratory of RNA Innovation, Science and Engineering, New Cornerstone Science Laboratory, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China

    Lin Shan & Ling-Ling Chen

  2. T. C. Jenkins Department of Biophysics, Johns Hopkins University, Baltimore, MD, USA

    Yunsheng Sun & Sarah A. Woodson

  3. School of Life Science and Biotechnology, Shanghai Jiao Tong University, Shanghai, China

    Ling-Ling Chen

  4. Shanghai Academy of Natural Sciences (SANS), Shanghai, China

    Ling-Ling Chen

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Glossary

01 site

A specific pre-rRNA processing site within the 5′ ETS, where endonucleolytic cleavage occurs during early ribosome biogenesis. According to this nomenclature, labels such as 01, A0 and 1 mark distinct cleavage positions along the pre-rRNA, whereas terms such as 01–A0 denote the spacer fragment bounded by those two sites.

DEAD-box RNA-dependent ATPases

A conserved family of ATP-hydrolysing enzymes that unwind RNA duplexes and modulate RNA–protein condensates. In the nucleolus, they coordinate pre-rRNA remodelling.

Intrinsically disordered regions

(IDRs) Flexible, low-complexity protein domains lacking fixed tertiary structure. In nucleolar proteins, IDRs mediate multivalent RNA interactions and facilitate condensate formation and microrheological properties.

Micropolarity

Local polarity within the nucleolus, reflecting the physicochemical properties of the immediate molecular environment surrounding nucleolar components or polarity-sensitive probes.

Microviscosity

The effective local viscosity within the nucleolus, representing the resistance experienced by molecules as they diffuse, rotate or rearrange within nucleolar compartments.

Pre-rRNA processing

Hierarchical maturation of primary rRNA transcripts through site-specific cleavages, modifications and folding to yield the 18S, 5.8S and 28S rRNAs. Maturation is coupled with ribosomal-subunit assembly.

Ribosomopathies

A group of congenital or acquired disorders caused by defects in ribosome biogenesis or function. These diseases often present with tissue-specific pathologies linked to nucleolar dysfunction.

Super-resolution microscopy

(SRM) Optical imaging techniques (for example, structured illumination microscopy, stimulated emission depletion microscopy, and stochastic optical reconstruction microscopy) that surpass the diffraction limit of visible light to reveal nanoscale nucleolar architecture and molecule distributions.

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Shan, L., Sun, Y., Woodson, S.A. et al. Elucidating structure–function relationships in the mammalian nucleolus. Nat Rev Mol Cell Biol (2026). https://doi.org/10.1038/s41580-026-00975-z

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