p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity
Abstract Cells must accurately and quickly detect DNA damage through a set of checkpoint mechanisms that enable repair and control proliferation. Heterogeneous levels of cellular stress and noisy signaling processes can lead to phenotypic variability but little is known about their role in underlyin...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-023-05585-5 |
| _version_ | 1827633391300771840 |
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| author | Nica Gutu Neha Binish Ulrich Keilholz Hanspeter Herzel Adrián E. Granada |
| author_facet | Nica Gutu Neha Binish Ulrich Keilholz Hanspeter Herzel Adrián E. Granada |
| author_sort | Nica Gutu |
| collection | DOAJ |
| description | Abstract Cells must accurately and quickly detect DNA damage through a set of checkpoint mechanisms that enable repair and control proliferation. Heterogeneous levels of cellular stress and noisy signaling processes can lead to phenotypic variability but little is known about their role in underlying proliferation heterogeneity. Here we study two previously published single cell datasets and find that cells encode heterogeneous levels of endogenous and exogenous DNA damage to shape proliferation heterogeneity at the population level. Using a comprehensive time series analysis of short- and long-term signaling dynamics of p53 and p21, we show that DNA damage levels are quantitatively translated into p53 and p21 signal parameters in a gradual manner. Analyzing instantaneous proliferation and signaling differences among equally-radiated cells, we identify time-localized changes in the period of p53 pulses that drive cells out of a low proliferative state. Our findings suggest a novel role of the p53-p21 network in quantitatively encoding DNA damage strength and fine-tuning proliferation trajectories. |
| first_indexed | 2024-03-09T14:58:57Z |
| format | Article |
| id | doaj.art-515cf06ef05642a1b35c6a797fecb919 |
| institution | Directory Open Access Journal |
| issn | 2399-3642 |
| language | English |
| last_indexed | 2024-03-09T14:58:57Z |
| publishDate | 2023-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj.art-515cf06ef05642a1b35c6a797fecb9192023-11-26T14:00:20ZengNature PortfolioCommunications Biology2399-36422023-11-016111110.1038/s42003-023-05585-5p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneityNica Gutu0Neha Binish1Ulrich Keilholz2Hanspeter Herzel3Adrián E. Granada4Charité Universitätsmedizin, Charité Comprehensive Cancer CenterCharité Universitätsmedizin, Charité Comprehensive Cancer CenterCharité Universitätsmedizin, Charité Comprehensive Cancer CenterCharité Universitätsmedizin, Charité Comprehensive Cancer CenterCharité Universitätsmedizin, Charité Comprehensive Cancer CenterAbstract Cells must accurately and quickly detect DNA damage through a set of checkpoint mechanisms that enable repair and control proliferation. Heterogeneous levels of cellular stress and noisy signaling processes can lead to phenotypic variability but little is known about their role in underlying proliferation heterogeneity. Here we study two previously published single cell datasets and find that cells encode heterogeneous levels of endogenous and exogenous DNA damage to shape proliferation heterogeneity at the population level. Using a comprehensive time series analysis of short- and long-term signaling dynamics of p53 and p21, we show that DNA damage levels are quantitatively translated into p53 and p21 signal parameters in a gradual manner. Analyzing instantaneous proliferation and signaling differences among equally-radiated cells, we identify time-localized changes in the period of p53 pulses that drive cells out of a low proliferative state. Our findings suggest a novel role of the p53-p21 network in quantitatively encoding DNA damage strength and fine-tuning proliferation trajectories.https://doi.org/10.1038/s42003-023-05585-5 |
| spellingShingle | Nica Gutu Neha Binish Ulrich Keilholz Hanspeter Herzel Adrián E. Granada p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity Communications Biology |
| title | p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity |
| title_full | p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity |
| title_fullStr | p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity |
| title_full_unstemmed | p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity |
| title_short | p53 and p21 dynamics encode single-cell DNA damage levels, fine-tuning proliferation and shaping population heterogeneity |
| title_sort | p53 and p21 dynamics encode single cell dna damage levels fine tuning proliferation and shaping population heterogeneity |
| url | https://doi.org/10.1038/s42003-023-05585-5 |
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