Enhanced DNA repair through droplet formation and p53 oscillations

Living organisms are constantly exposed to DNA damage, and optimal repair is therefore crucial. A characteristic hallmark of the response is the formation of sub-compartments around the site of damage, known as foci. Following multiple DNA breaks, the transcription factor p53 exhibits oscillations i...

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Bibliographic Details
Published in:Cell 2022-11, Vol.185 (23), p.4394-4408.e10
Main Authors: Heltberg, Mathias S., Lucchetti, Alessandra, Hsieh, Feng-Shu, Minh Nguyen, Duy Pham, Chen, Sheng-hong, Jensen, Mogens H.
Format: Article
Language:English
Subjects:
DNA
DNA Damage
DNA Repair
droplets
oscillations
Ostwald ripening
p53 dynamics
periodicity
phase transitions
Proto-Oncogene Proteins c-mdm2 - genetics
Proto-Oncogene Proteins c-mdm2 - metabolism
response
Signal Transduction - physiology
transcription factors
Tumor Suppressor Protein p53 - metabolism
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Summary:Living organisms are constantly exposed to DNA damage, and optimal repair is therefore crucial. A characteristic hallmark of the response is the formation of sub-compartments around the site of damage, known as foci. Following multiple DNA breaks, the transcription factor p53 exhibits oscillations in its nuclear concentration, but how this dynamics can affect the repair remains unknown. Here, we formulate a theory for foci formation through droplet condensation and discover how oscillations in p53, with its specific periodicity and amplitude, optimize the repair process by preventing Ostwald ripening and distributing protein material in space and time. Based on the theory predictions, we reveal experimentally that the oscillatory dynamics of p53 does enhance the repair efficiency. These results connect the dynamical signaling of p53 with the microscopic repair process and create a new paradigm for the interplay of complex dynamics and phase transitions in biology. [Display omitted] •p53 oscillations optimize DNA repair compared to cells with sustained levels•Enhanced DNA repair efficiency may be achieved by suppression of Ostwald ripening•Natural p53 periodicity and amplitude enable optimal distribution of repair material•Oscillations enhance robustness of DNA damage response in stochastic environments A theory explains how oscillations in p53 nuclear abundance optimize DNA damage repair.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2022.10.004