Poly(ADP-ribose) drives condensation of FUS via a transient interaction

Kevin Rhine; Morgan Dasovich; Joseph Yoniles; Mohsen Badiee; Sophie Skanchy; Laura R Ganser; Yingda Ge; Charlotte M Fare; James Shorter; Anthony K L Leung; Sua Myong

doi:10.1016/j.molcel.2022.01.018

Poly(ADP-ribose) drives condensation of FUS via a transient interaction

Mol Cell. 2022 Mar 3;82(5):969-985.e11. doi: 10.1016/j.molcel.2022.01.018. Epub 2022 Feb 18.

Authors

Affiliations

¹ Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biology, Johns Hopkins University, Baltimore, MD 21218, USA.
² Chemistry-Biology Interface Program, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Chemistry, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
³ Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA.
⁴ Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
⁵ Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
⁶ Chemistry-Biology Interface Program, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Molecular Biology and Genetics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. Electronic address: anthony.leung@jhu.edu.
⁷ Program in Cell, Molecular, Developmental Biology, and Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA; Department of Biophysics, Johns Hopkins University, Baltimore, MD 21218, USA; Physics Frontier Center (Center for the Physics of Living Cells), University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA. Electronic address: smyong@jhu.edu.

Abstract

Poly(ADP-ribose) (PAR) is an RNA-like polymer that regulates an increasing number of biological processes. Dysregulation of PAR is implicated in neurodegenerative diseases characterized by abnormal protein aggregation, including amyotrophic lateral sclerosis (ALS). PAR forms condensates with FUS, an RNA-binding protein linked with ALS, through an unknown mechanism. Here, we demonstrate that a strikingly low concentration of PAR (1 nM) is sufficient to trigger condensation of FUS near its physiological concentration (1 μM), which is three orders of magnitude lower than the concentration at which RNA induces condensation (1 μM). Unlike RNA, which associates with FUS stably, PAR interacts with FUS transiently, triggering FUS to oligomerize into condensates. Moreover, inhibition of a major PAR-synthesizing enzyme, PARP5a, diminishes FUS condensation in cells. Despite their structural similarity, PAR and RNA co-condense with FUS, driven by disparate modes of interaction with FUS. Thus, we uncover a mechanism by which PAR potently seeds FUS condensation.

Keywords: FUS; LLPS; PARP5a; PARylation; RNA; condensation; length dependence; poly(ADP-ribose); stress response; transient interaction.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Amyotrophic Lateral Sclerosis* / genetics
Humans
Poly Adenosine Diphosphate Ribose* / metabolism
RNA / genetics
RNA-Binding Protein FUS / metabolism

Substances

FUS protein, human
RNA-Binding Protein FUS
Poly Adenosine Diphosphate Ribose
RNA

Abstract

Publication types

MeSH terms

Substances

Grants and funding