Partitioning of cancer therapeutics in nuclear condensates

Klein, I.; Boija, Ann; Afeyan, Lena K.; Hawken, Susana Wilson; Fan, Mengyang; Dall’Agnese, Alessandra; Oksuz, Ozgur; Henninger, Jonathan E.; Shrinivas, Krishna; Sabari, Benjamin R.; Sagi, Ido; Clark, Victoria; Platt, Jesse M.; Kar, Mrityunjoy; McCall, Patrick M.; Zamudio, Alicia V.; Manteiga, John C.; Coffey, Eliot L.; Li, Charles; Hannett, Nancy M.; Guo, Yang; Decker, Tim-Michael; Lee, Tong Ihn; Zhang, Tinghu; Weng, Jing-Ke; Taatjes, Dylan J.; Chakraborty, Arup K.; Sharp, Phillip A.; Chang, Young Tae; Hyman, Anthony; Gray, Nathanael S.; Young, Richard A.

doi:10.1126/science.aaz4427

Cited by 368 publications

(314 citation statements)

References 67 publications

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“…Biomolecular condensates accommodate hundreds of distinct molecular components and considerable effort is being invested to understand the determinants of compositional control of distinct condensates (1, 9,15,17,19,34,36,[44][45][46][47][48][49][50]. Partition coefficients have become the workhorse quantities that are used to map the compositional biases of condensates (29,34,48,51). Although, PCs are beneficial for compositional profiling of condensates, they do not yield insights as to whether the non-scaffold components of condensates act as modulators of scaffold phase behavior.…”

Section: Discussionmentioning

confidence: 99%

“…Answers to these questions are directly relevant to an improved understanding of how ligands contribute to the modulation and regulation of the phase behavior of scaffolds. They are also directly relevant to the design of therapeutics that alter the phase behavior of scaffolds (33,34). In this schematic, we assume that the scaffolds undergo phase separation and form two distinct phases: the dilute phase (red), A, and the dense phase (blue), B.…”

Section: Significancementioning

confidence: 99%

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Ligand Effects on Phase Separation of Multivalent Macromolecules

Ruff

Dar

Pappu

2020

Preprint

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Biomolecular condensates are thought to form via phase transitions of multivalent macromolecules. Components of condensates have been classified as scaffolds and clients. In this classification, scaffolds drive condensate formation whereas clients partition into condensates. However, non-scaffold molecules can be ligands that modulate the phase behavior of scaffolds via preferential binding across phase boundaries. Here, we present computational results that explain how preferential binding of ligands to scaffold molecules in different phases can impact phase separation and the compositions of dense phases. We show that phase separation is destabilized by monovalent ligands. In contrast, multivalent ligands, depending on their mode of binding, can stabilize phase separation by serving as crosslinkers that network scaffold molecules. We also find that concentrations of scaffolds within dense phases are generally diluted by ligands. This arises because ligands destabilize condensates by preferentially binding to scaffolds in the dilute phase or because ligands have to be accommodated within dense phases when they bind preferentially to scaffolds in the dense phase. Importantly, we show that partition coefficients, which are routinely used for compositional profiling of condensates, say nothing about the regulatory impact of ligands on the phase behavior of scaffolds. Therefore, instead of measuring partition coefficients it becomes imperative to measure how ligands impact threshold concentrations of scaffolds. These measurements, performed as a function of ligand concentration, will help with understanding the regulation of condensates and enable the design of molecules that impact condensate formation or dissolution.

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Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

Ligand Effects on Phase Separation of Multivalent Macromolecules

Ruff

Dar

Pappu

2020

Preprint

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“…According to our results, we speculate that the LLPS characteristics of N protein may be one of the underlying reasons for the failure of many anti-coronavirus drugs. A related evidence comes from a recent study showing that a number of antineoplastic drugs cannot freely diffuse, but rather become partitioned in specific protein condensates in vitro 50 . This result supports the hypothesis that altering the biophysical properties of condensates may improve the distribution and efficacy of drugs.…”

Section: Discussionmentioning

confidence: 99%

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

Zhao

Zhang

et al. 2020

Preprint

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The ongoing coronavirus disease 2019 (COVID-19) pandemic has raised an urgent need to develop effective therapeutics against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). As a potential antiviral drug target, the nucleocapsid (N) protein of SARS-CoV-2 functions as a viral RNA chaperone and plays vital and multifunctional roles during the life cycle of coronavirus1-3. In this study, we discovered that the N protein of SARS-CoV-2 undergoes liquid-liquid phase separation (LLPS) both in vitro and in vivo, which is further modulated by viral RNA. In addition, we found that, the core component of the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2, nsp12, preferentially partitions into the N protein condensates. Moreover, we revealed that, two small molecules, i.e., CVL218 and PJ34, can be used to intervene the N protein driven phase separation and loosen the compact structures of the condensates of the N-RNA-nsp12 complex of SARS-CoV-2. The discovery of the LLPS-mediated interplay between N protein and nsp12 and the corresponding modulating compounds illuminates a feasible way to improve the accessibility of antiviral drugs (e.g., remdesivir) to their targets (e.g., nsp12/RdRp), and thus may provide useful hints for further development of effective therapeutic strategies against SARS-CoV-2.

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“…Hence, the fundamental mechanism controlling PGC-1α function discovered in this work might have important implication in the development of strategies to improve energy metabolism under pathological conditions, e.g. by leveraging pharmacological approaches aimed at the selective modulation of transcriptional condensates 28 .…”

Section: Mainmentioning

confidence: 92%

RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

Pérez-Schindler

Kohl

Schneider-Heieck

et al. 2020

Preprint

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The peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) integrates environmental cues by controlling complex transcriptional networks in various metabolically active tissues. However, it is unclear how a transcriptional coregulator coordinates dynamic biological programs in response to multifaceted stimuli such as endurance training or fasting. Here, we discovered a central function of the poorly understood C-terminal domain (CTD) of PGC-1α to bind RNAs and assemble multi-protein complexes. Surprisingly, in addition to controlling the coupling of transcription and processing of target genes, RNA binding is indispensable for the recruitment of PGC-1α to chromatin into liquid-like nuclear condensates, which compartmentalize and regulate active transcription. These results demonstrate a hitherto unsuspected molecular mechanism by which complexity in the regulation of large transcriptional networks by PGC-1α is achieved. These findings are not only essential for the basic understanding of transcriptional coregulator-driven control of biological programs, but will also help to devise new strategies to modulate these processes in pathological contexts in which PGC-1α function is dysregulated, such as type 2 diabetes, cardiovascular diseases or skeletal muscle wasting.

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Partitioning of cancer therapeutics in nuclear condensates

Cited by 368 publications

References 67 publications

Ligand Effects on Phase Separation of Multivalent Macromolecules

Ligand Effects on Phase Separation of Multivalent Macromolecules

Understanding the phase separation characteristics of nucleocapsid protein provides a new therapeutic opportunity against SARS-CoV-2

RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

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