Abstract
Biomolecular condensates, sometimes also known as membraneless organelles (MLOs), can form through weak multivalent intermolecular interactions of proteins and nucleic acids, a process often associated with liquid–liquid phase separation. Biomolecular condensates are emerging as sites and regulatory platforms of vital cellular functions, including transcription and RNA processing. In the first part of this Review, we comprehensively discuss how alternative splicing regulates the formation and properties of condensates, and conversely the roles of biomolecular condensates in splicing regulation. In the second part, we focus on the spatial connection between splicing regulation and nuclear MLOs such as transcriptional condensates, splicing condensates and nuclear speckles. We then discuss key studies showing how splicing regulation through biomolecular condensates is implicated in human pathologies such as neurodegenerative diseases, different types of cancer, developmental disorders and cardiomyopathies, and conclude with a discussion of outstanding questions pertaining to the roles of condensates and MLOs in splicing regulation and how to experimentally study them.
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Acknowledgements
The work by H.J. on AKAP95 condensates was supported by the Department of Defense Breast Cancer Research Program (Breakthrough Award BC190343). J.G. is supported by The University of North Carolina at Chapel Hill (start-up funds and Jefferson Pilot Award), the National Institutes of Health (NIH) (R01-GM130866) and the National Science Foundation (NSF) (CAREER award 2239056).
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Glossary
- Amyloid aggregates
-
Fibrillar protein aggregates typically 7–13 nm in diameter and a β-sheet secondary structure.
- Limb-girdle muscular dystrophy
-
A large group of genetic diseases characterized by muscle weakness and wasting.
- Nuclear speckles
-
Dynamic, membraneless subnuclear compartments that are enriched in splicing factors and other proteins involved in transcription, RNA processing and reversible protein phosphorylation.
- Scaffold and client
-
In the context of condensates, scaffold molecules (proteins or long non-coding RNAs (lncRNAs)) are required for and drive condensate formation; client molecules are not essential for condensate formation, but partition into the condensates through their interactions with the scaffold or other client molecules.
- Stress granules
-
Biomolecular condensates of mRNAs stalled in translation and RNA-binding proteins (RBPs), which form in the cytoplasm following physical, mechanical or chemical stress.
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Giudice, J., Jiang, H. Splicing regulation through biomolecular condensates and membraneless organelles. Nat Rev Mol Cell Biol (2024). https://doi.org/10.1038/s41580-024-00739-7
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DOI: https://doi.org/10.1038/s41580-024-00739-7
