Functional interactions between scaffold proteins, noncoding RNAs, and genome loci induce liquid‐liquid phase separation as organizing principle for 3‐dimensional nuclear architecture: implications in cancer

Abstract

The eukaryotic cell nucleus consists of functionally specialized subcompartments. These nuclear sub‐compartments are biomolecular aggregates built of proteins, transcripts, and specific genome loci. The structure and function of each nuclear subcompartment are defined by the composition and dynamic interaction between these 3 components. The spatio‐temporal localization of biochemical reactions into membraneless nuclear subcompartments can be achieved through liquid‐liquid phase separation. Based on this organizing principle, nuclear sub‐compartments are droplet‐like structures that adopt spherical shapes, flow, and fuse like liquids or gels. In the present review, we bring into the spotlight seminal works elucidating the functional interactions between scaffold proteins, noncoding RNAs, and genomic loci, thereby inducing liquid‐liquid phase separation as an organizing principle for 3‐dimensional nuclear architecture. We also discuss the implications in different cancer types as well as the potential use of this knowledge to develop novel therapeutic strategies against cancer.—Rubio, K., Dobersch, S., Barreto, G. Functional interactions between scaffold proteins, noncoding RNAs, and genome loci induce liquid‐liquid phase separation as organizing principle for 3‐dimensional nuclear architecture: implications in cancer. FASEB J. 33, 5814–5822 (2019). http://www.fasebj.org

Therapeutics—how to treat phase separation-associated diseases

“…Molecular detail of these mechanisms are still emerging, but sit as part of wider evidence for likely LLPS-cancer links. Perturbation of any of the membraneless nuclear compartments, whether large (the nucleolus or heterochromatin) or small (transcription factories, DNA damage foci and, in particular, superenhancers [42]) could alter gene expression and contribute to cancer [43][44][45][46]. More generally, mechanisms involving LLPS in cell signalling [9,17] can also underlie signalling which, when defective, may contribute to oncogenesis [13].…”

MALAT1 Long Non-Coding RNA: Functional Implications

“…[10]. More recent evidence suggests that lncRNAs actively contribute to phase separation in large ribonucleoprotein complexes giving rise to membrane-less organelles inside the cell [11][12][13][14]. Given the remarkable diversity of this class of RNAs, it is reasonable to envision that they contribute in a structural, functional, and/or regulatory capacity in a wide range of cellular/nuclear processes [15].…”

Inactivation of nuclear histone deacetylases by EP300 disrupts the MiCEE complex in idiopathic pulmonary fibrosis

“…Beyond its association to several human diseases, miRNAs are considered key diagnostic markers as well as dynamic regulators of phase separation as the organizing principle for tridimensional nuclear architecture 21 . Increasing evidence of mature miRNAs in the nucleus suggests a novel function in sub-nuclear compartments of mammalian cells 22–24 . In our previous work 25 we characterize a multicomponent RNA–protein complex containing miRNA–ncRNA duplexes, the exosome-associated protein C1D, the nuclear-specific exosome subunit EXOSC10 (also known as RRP6), and the histone methyl transferase EZH2 (enhancer of zeste homolog 2).…”