Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and in vitro studies, we show the spatiotemporal formation and material properties of p53 condensates that might dictate its function. In particular, p53 forms liquid-like condensates in the nucleus of cells, which can bind to DNA and perform transcriptional activity. However, cancer-associated mutations promote misfolding and partially rigidify the p53 condensates with impaired DNA binding ability. Irrespective of wild-type and mutant forms, the partitioning of p53 into cytoplasm leads to the condensate formation, which subsequently undergoes rapid solidification. In vitro studies show that abundant nuclear components such as RNA and nonspecific DNA promote multicomponent phase separation of the p53 core domain and maintain their liquid-like property, whereas specific DNA promotes its dissolution into tetrameric functional p53. This work provides mechanistic insights into how the life cycle and DNA binding properties of p53 might be regulated by phase separation.

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Publication Details

Journal
Science Advances
Published
2024-12-11
DOI
https://doi.org/10.1126/sciadv.ads0427
Citations
16
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
3.74
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article

Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation

Laxmikant Gadhe, Pradeep Kadu, A. Paul, Shalaka Masurkar et al.
16 citations
Science Advances
RNA Research and Splicing
3.74
article

Nucleo-cytoplasmic environment modulates spatiotemporal p53 phase separation

Laxmikant Gadhe, Pradeep Kadu, A. Paul, Shalaka Masurkar, Ranjit Shaw, Ajay Singh Sawner, Kundan Sengupta, Satyaprakash Pandey, Nitisha Gahlot, Arpita Bhattacharyya, Samir K. Maji, Shinjinee Sengupta, Ambuja Navalkar, Arunima Sakunthala, Manisha Poudyal, Semanti Mukherjee, Jyoti Devi, Samprikta Manna, Komal Patel, Debalina Datta
article en
16 citations

Abstract

Liquid-liquid phase separation of various transcription factors into biomolecular condensates plays an essential role in gene regulation. Here, using cellular models and in vitro studies, we show the spatiotemporal formation and material properties of p53 condensates that might dictate its function. In particular, p53 forms liquid-like condensates in the nucleus of cells, which can bind to DNA and perform transcriptional activity. However, cancer-associated mutations promote misfolding and partially rigidify the p53 condensates with impaired DNA binding ability. Irrespective of wild-type and mutant forms, the partitioning of p53 into cytoplasm leads to the condensate formation, which subsequently undergoes rapid solidification. In vitro studies show that abundant nuclear components such as RNA and nonspecific DNA promote multicomponent phase separation of the p53 core domain and maintain their liquid-like property, whereas specific DNA promotes its dissolution into tetrameric functional p53. This work provides mechanistic insights into how the life cycle and DNA binding properties of p53 might be regulated by phase separation.

Science AdvancesVol. 10(50)
Indian Institute of Technology Bombay (IN), Indian Institute of Science Education and Research Pune (IN)
Responsible consumption and production
Openalex Percentile: Top 6%
RNA Research and Splicing
3.74
DOIOpen Access PDFOpenAlex
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