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

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  • Matthias Altmeyer

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
    Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich)

  • Kai J. Neelsen

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Federico Teloni

    (Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich)

  • Irina Pozdnyakova

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Stefania Pellegrino

    (Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich)

  • Merete Grøfte

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Maj-Britt Druedahl Rask

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Werner Streicher

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
    Present address: Novozymes A/S, Krogshoejvej 36, DK-2880 Bagsverd, Denmark)

  • Stephanie Jungmichel

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Michael Lund Nielsen

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

  • Jiri Lukas

    (Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen)

Abstract

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.

Suggested Citation

  • Matthias Altmeyer & Kai J. Neelsen & Federico Teloni & Irina Pozdnyakova & Stefania Pellegrino & Merete Grøfte & Maj-Britt Druedahl Rask & Werner Streicher & Stephanie Jungmichel & Michael Lund Nielse, 2015. "Liquid demixing of intrinsically disordered proteins is seeded by poly(ADP-ribose)," Nature Communications, Nature, vol. 6(1), pages 1-12, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms9088
    DOI: 10.1038/ncomms9088
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    Cited by:

    1. Yun-Long Wang & Wan-Wen Zhao & Shao-Mei Bai & Li-Li Feng & Shu-Ying Bie & Li Gong & Fang Wang & Ming-Biao Wei & Wei-Xing Feng & Xiao-Lin Pang & Cao-Litao Qin & Xin-Ke Yin & Ying-Nai Wang & Weihua Zhou, 2022. "MRNIP condensates promote DNA double-strand break sensing and end resection," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Zhaowei Yu & Qi Wang & Qichen Zhang & Yawen Tian & Guo Yan & Jidong Zhu & Guangya Zhu & Yong Zhang, 2024. "Decoding the genomic landscape of chromatin-associated biomolecular condensates," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    3. Marie-France Langelier & Ramya Billur & Aleksandr Sverzhinsky & Ben E. Black & John M. Pascal, 2021. "HPF1 dynamically controls the PARP1/2 balance between initiating and elongating ADP-ribose modifications," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

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