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      Partitioning of cancer therapeutics in nuclear condensates

      Author(s): 1 , 2 , 1 , 1 , 3 , 1 , 3 , 4 , 5 , 1 , 1 , 1 , 6 , 7 , 1 , 1 , 1 , 8 , 1 , 9 , 10 , 10 , 11 , 12 , 1 , 3 , 1 , 3 , 1 , 3 , 1 , 3 , 1 , 1 , 13 , 1 , 4 , 5 , 1 , 3 , 13 , 6 , 7 , 14 , 15 , 16 , 3 , 17 , 18 , 11 , 19 , 4 , 5 , 1 , 3
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      Journal: Science
      Publisher: American Association for the Advancement of Science (AAAS)

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          Abstract

          The nucleus contains diverse phase-separated condensates that compartmentalize and concentrate biomolecules with distinct physicochemical properties. Here, we investigated whether condensates concentrate small-molecule cancer therapeutics such that their pharmacodynamic properties are altered. We found that antineoplastic drugs become concentrated in specific protein condensates in vitro and that this occurs through physicochemical properties independent of the drug target. This behavior was also observed in tumor cells, where drug partitioning influenced drug activity. Altering the properties of the condensate was found to affect the concentration and activity of drugs. These results suggest that selective partitioning and concentration of small molecules within condensates contributes to drug pharmacodynamics and that further understanding of this phenomenon may facilitate advances in disease therapy.

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          Sequence Determinants of Intracellular Phase Separation by Complex Coacervation of a Disordered Protein.

          Chi Pak, Martyna Kosno, Alex S. Holehouse … (2016)
          Liquid-liquid phase separation, driven by collective interactions among multivalent and intrinsically disordered proteins, is thought to mediate the formation of membrane-less organelles in cells. Using parallel cellular and in vitro assays, we show that the Nephrin intracellular domain (NICD), a disordered protein, drives intracellular phase separation via complex coacervation, whereby the negatively charged NICD co-assembles with positively charged partners to form protein-rich dense liquid droplets. Mutagenesis reveals that the driving force for phase separation depends on the overall amino acid composition and not the precise sequence of NICD. Instead, phase separation is promoted by one or more regions of high negative charge density and aromatic/hydrophobic residues that are distributed across the protein. Many disordered proteins share similar sequence characteristics with NICD, suggesting that complex coacervation may be a widely used mechanism to promote intracellular phase separation.
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            m 6 A enhances the phase separation potential of mRNA

            Ryan Ries, Sara Zaccara, Pierre Klein … (2019)
            N 6-methyladenosine (m6A) is the most prevalent modified nucleotide in mRNA 1,2 , with ~25% of mRNAs containing at least one m6A. Methylation of mRNA to form m6A is required for diverse cellular and physiological processes 3 . Although the presence of m6A in an mRNA can affect its fate in different ways, it is unclear how m6A directs this process and why the effects of m6A can vary in different cellular contexts. Here we show that the cytosolic m6A-binding proteins, YTHDF1–3, undergo liquid-liquid phase separation (LLPS) in vitro and in cells. This LLPS is markedly enhanced by mRNAs that contain multiple, but not single, m6A residues. Polymethylated mRNAs act as a multivalent scaffold for binding YTHDF proteins, juxtaposing their low-complexity domains, leading to phase separation. The resulting mRNA-YTHDF complexes then partition into different endogenous phase-separated compartments, such as P-bodies, stress granules, or neuronal RNA granules. m6A-mRNA is subject to compartment-specific regulation, including reduced mRNA stability and translation. These studies reveal that the number and distribution of m6A sites in cellular mRNAs can regulate and influence the composition of the phase-separated transcriptome. Additionally, these findings indicate that the cellular properties of m6A-modified mRNAs are governed by liquid-liquid phase separation principles.
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              Organization and regulation of gene transcription

              Patrick Cramer (2019)
              The regulated transcription of genes determines cell identity and function. Recent structural studies have elucidated mechanisms that govern the regulation of transcription by RNA polymerases during the initiation and elongation phases. Microscopy studies have revealed that transcription involves the condensation of factors in the cell nucleus. A model is emerging for the transcription of protein-coding genes in which distinct transient condensates form at gene promoters and in gene bodies to concentrate the factors required for transcription initiation and elongation, respectively. The transcribing enzyme RNA polymerase II may shuttle between these condensates in a phosphorylation-dependent manner. Molecular principles are being defined that rationalize transcriptional organization and regulation, and that will guide future investigations.
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                Author and article information

                Journal
                Title: Science
                Abbreviated Title: Science
                Publisher: American Association for the Advancement of Science (AAAS)
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date Created: June 18 2020
                Publication date Created: June 19 2020
                Publication date (Electronic): June 18 2020
                Publication date (Print): June 19 2020
                Volume: 368
                Issue: 6497
                Pages: 1386-1392
                Affiliations
                [1 ]Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
                [2 ]Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
                [3 ]Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [4 ]Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
                [5 ]Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
                [6 ]Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [7 ]Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [8 ]Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
                [9 ]Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
                [10 ]Max Planck Institute for the Physics of Complex Systems, 01187 Dresden, Germany.
                [11 ]Max Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
                [12 ]Center for Systems Biology Dresden, 01307 Dresden, Germany.
                [13 ]Department of Biochemistry, University of Colorado, Boulder, CO 80303, USA.
                [14 ]Department of Physics, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [15 ]Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [16 ]Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [17 ]Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
                [18 ]Department of Chemistry, Pohang University of Science and Technology, and Center for Self-assembly and Complexity, Institute for Basic Science (IBS), Pohang 37673, Republic of Korea.
                [19 ]Cluster of Excellence Physics of Life, Technical University of Dresden, 01062 Dresden, Germany.
                Article
                DOI: 10.1126/science.aaz4427
                PMC ID: 7735713
                PubMed ID: 32554597
                SO-VID: 14dc7c3e-a513-4711-8415-122554cb9528
                Copyright © © 2020
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                http://www.sciencemag.org/about/science-licenses-journal-article-reuse

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