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Poly(Adp-Ribose) Drives Condensation of Fus Via a Transient Interaction

49 Pages Posted: 20 Jul 2021 Publication Status: Published

See all articles by Kevin Rhine

Kevin Rhine

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics

Morgan Dasovich

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics

Joseph Yoniles

Johns Hopkins University - Department of Biophysics

Mohsen Badiee

Johns Hopkins University - Department of Biochemistry and Molecular Biology

Sophie Skanchy

Johns Hopkins University - Department of Biophysics

Laura Ganser

Johns Hopkins University - Department of Biophysics

Charlotte Fare

University of Pennsylvania - Department of Biochemistry and Biophysics

James Shorter

University of Pennsylvania - Department of Biochemistry and Biophysics

Anthony K. L. Leung

Johns Hopkins University - Department of Biochemistry and Molecular Biology; Johns Hopkins University - McKusick-Nathans Institute of the Department of Genetic Medicine

Sua Myong

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics

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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.

Suggested Citation

Rhine, Kevin and Dasovich, Morgan and Yoniles, Joseph and Badiee, Mohsen and Skanchy, Sophie and Ganser, Laura and Fare, Charlotte and Shorter, James and Leung, Anthony K. L. and Myong, Sua, Poly(Adp-Ribose) Drives Condensation of Fus Via a Transient Interaction. Available at SSRN: https://ssrn.com/abstract=3890382 or http://dx.doi.org/10.2139/ssrn.3890382
This version of the paper has not been formally peer reviewed.

Kevin Rhine

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics ( email )

United States

Morgan Dasovich

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics ( email )

United States

Joseph Yoniles

Johns Hopkins University - Department of Biophysics ( email )

3400 N. Charles Street
110 Jenkins Hall
Baltimore, MD 21218
United States

Mohsen Badiee

Johns Hopkins University - Department of Biochemistry and Molecular Biology ( email )

615 N. Wolfe Street
Baltimore, MD 21205
United States

Sophie Skanchy

Johns Hopkins University - Department of Biophysics

Baltimore, MD 20036-1984
United States

Laura Ganser

Johns Hopkins University - Department of Biophysics ( email )

3400 N. Charles Street
110 Jenkins Hall
Baltimore, MD 21218
United States

Charlotte Fare

University of Pennsylvania - Department of Biochemistry and Biophysics ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

James Shorter

University of Pennsylvania - Department of Biochemistry and Biophysics ( email )

423 Guardian Drive
Philadelphia, PA 19104
United States

Anthony K. L. Leung

Johns Hopkins University - Department of Biochemistry and Molecular Biology ( email )

615 N. Wolfe Street
Baltimore, MD 21205
United States

Johns Hopkins University - McKusick-Nathans Institute of the Department of Genetic Medicine ( email )

United States

Sua Myong (Contact Author)

Johns Hopkins University - Program in Cell, Molecular, Developmental Biology, and Biophysics

United States

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