Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)

Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that th...

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Published in:Nature communications Vol. 6; no. 1; p. 8088
Main Authors: Altmeyer, Matthias, Neelsen, Kai J., Teloni, Federico, Pozdnyakova, Irina, Pellegrino, Stefania, Grøfte, Merete, Rask, Maj-Britt Druedahl, Streicher, Werner, Jungmichel, Stephanie, Nielsen, Michael Lund, Lukas, Jiri
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 19.08.2015
Nature Publishing Group
Nature Pub. Group
Subjects:
14/1
14/28
14/35
14/63
631/337/1427
631/45
631/57/2269
Adenosine diphosphate
Biopolymers
Cell Line, Tumor
Cloning, Molecular
Deoxyribonucleic acid
DNA
DNA Damage
Gene Expression Regulation - physiology
Humanities and Social Sciences
Humans
multidisciplinary
Nucleic acids
Poly Adenosine Diphosphate Ribose - chemistry
Protein Conformation
Protein Structure, Tertiary
Proteins - chemistry
Proteins - genetics
Proteins - metabolism
Science
Science (multidisciplinary)
ISSN:2041-1723, 2041-1723
Online Access:Get full text
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Summary:Intrinsically disordered proteins can phase separate from the soluble intracellular space, and tend to aggregate under pathological conditions. The physiological functions and molecular triggers of liquid demixing by phase separation are not well understood. Here we show in vitro and in vivo that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing. PAR levels are markedly induced at sites of DNA damage, and we provide evidence that PAR-seeded liquid demixing results in rapid, yet transient and fully reversible assembly of various intrinsically disordered proteins at DNA break sites. Demixing, which relies on electrostatic interactions between positively charged RGG repeats and negatively charged PAR, is amplified by aggregation-prone prion-like domains, and orchestrates the earliest cellular responses to DNA breakage. We propose that PAR-seeded liquid demixing is a general mechanism to dynamically reorganize the soluble nuclear space with implications for pathological protein aggregation caused by derailed phase separation. Intrinsically disordered proteins can phase separate from the soluble intracellular space. Here the authors show that the nucleic acid-mimicking biopolymer poly(ADP-ribose) (PAR) nucleates intracellular liquid demixing and orchestrates the earliest cellular responses to DNA breakage.
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Present address: Novozymes A/S, Krogshoejvej 36, DK-2880 Bagsverd, Denmark
ISSN:2041-1723
2041-1723
DOI:10.1038/ncomms9088