1 avril

Functions of biomolecular condensates assembled in response to DNA damage

Le 1 avril - 11h-23h
Centre de recherche - Paris - Amphithéâtre Hélène Martel-Massignac (BDD)
11 rue Pierre et Marie Curie - 75005 Paris

DNA repair mechanisms are crucial for organismal health and survival. All living organisms have evolved a multitude of mechanisms to repair alterations in the primary structure of DNA. DNA damage response (DDR) proteins often accumulate in nuclear foci seemingly similar to biomolecular condensates, but the intrinsic molecular organization and the functions that arise specifically from the assembly of DDR foci remain poorly understood. Biomolecular condensates compartmentalize hundreds of different molecules in multiple copies, in the absence of a surrounding membrane. I will present evidence suggesting that DDR foci represent biomolecular condensates assembled via cooperative site-specific interactions of scaffold proteins to regulate the localization and the timing of biochemical reactions.

We reported that the multivalent protein scaffold TOPBP1 self-assembles extensively to yield nuclear condensates, and that TOPBP1 condensation triggers ATR/Chk1 through a condensation-dependent amplification mechanism (Frattini et al., 2021). More recently, we obtained evidence that the multifunctional DNA repair protein SLX4 forms liquid-like nuclear condensates driven by site-specific protein interactions. Using an optogenetic system, we found that SLX4 condensation compartmentalizes the SUMO/ubiquitination system and amplifies the modification of substrate proteins. SLX4 condensation promotes the extraction of Topoisomerase 1 protein DNA crosslinks from chromatin, as well as the collapse of replication forks. We propose that spatiotemporal control of the SUMO/STUbL system by SLX4 condensation ensures the selective degradation of proteins. Thus, multiple site-specific interactions mediated by a scaffold protein can promote the local assembly of membrane-less compartments at DNA damage sites, define their composition, and control biochemical reactions.

Institute of Human Genetics
Invité(es) par
Group Leader
Institut Curie