Phase Separation and Oscillations in DNA Damage Response

Descripción del proyecto

La física de la respuesta al daño en el ADN

El mecanismo de respuesta al daño del ADN mantiene la integridad genómica y evita que las mutaciones deletéreas pasen a las células hijas. Favorece la reparación del ADN por medio de proteínas que se acumulan en las roturas de doble cadena del ADN, así como a través del inicio de la detención del ciclo celular. A pesar de su importancia, no se conoce en detalle la física que subyace a la respuesta al daño en el ADN. En el proyecto PHOSCIL, financiado por el Consejo Europeo de Investigación, se busca colmar esta brecha del conocimiento mediante el estudio de la interacción de las proteínas para formar condensados. El objetivo es comprender los principios físicos que regulan la reparación y el control del ciclo celular y su papel en el control del destino celular.

Objetivo

DNA damage response is a crucial function in living organisms, essential for maintaining genomic integrity. Two key processes prevent damage from propagating through generations: 1) DNA repair and 2) regulation of the cell cycle. Recent discoveries reveal that following DNA double-strand breaks, cells form biomolecular condensates at the site of damage through liquid-liquid phase separation. Another hallmark of the response is the initiation of oscillatory p53 concentration leading to cell cycle arrest. Despite being one of the most basic responses in cells, the physical mechanisms underlying this remains poorly understood as does the interplay between repair and regulation.
I aim to derive the basic principles for condensates interacting with dynamical and oscillatory concentration fields. Here I will uncover how cells use fundamental mechanisms of physics to control formation and maintenance of condensates and how the emergence of oscillations can facilitate this task.
The main highlights of PHOSCIL are the following:
Revealing the physical mechanisms and inferring observables of condensate formation, by creating new methods for analysis, guided by theoretical models applied to novel experiments.
Discovery of out-of-equillibrium phenomena of oscillatory and dynamic fields and their interactions with phase separation, generating conceptual advances in our understanding of biophysical systems.
Uncovering the functional roles of phase sparation and oscillation on both repair and cell cycle regulation, advancing our fundamental understanding of, and ability to influence, cell fate decisions.
To succesfully take these ambitious steps, I will combine theory and experiments that, taken together, will uncover novel concepts in the physics of phase separating systems and define a new chapter in our understanding of the DNA damage response.