Phase Separation and Oscillations in DNA Damage Response

Projektbeschreibung

Die Physik der DNS-Schadensantwort

Der Mechanismus der DNS-Schadensantwort ist für die Aufrechterhaltung der genomischen Integrität verantwortlich und verhindert, dass schädliche Mutationen an Tochterzellen weitergegeben werden. Dieser Mechanismus beinhaltet die DNS-Reparatur, die durch Proteine vermittelt wird, die sich an DNS-Doppelstrangbrüchen anreichern, sowie die Einleitung eines Zellzyklusarrests. Ungeachtet ihrer Bedeutung ist nur wenig über die physikalischen Mechanismen bekannt, die die DNS-Schadensantwort steuern. Das Ziel des ERC-finanzierten Projekts PHOSCIL lautet, diese Wissenslücke zu schließen, wobei untersucht wird, wie Proteine bei der Bildung von Kondensaten interagieren. Es gilt, die physikalischen Prinzipien zu verstehen, die Reparatur und Zellzykluskontrolle regulieren, und wie sie wichtige Entscheidungen über das Zellschicksal beeinflussen.

Ziel

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.