The Role of Liquid Phase Separation in DNA Damage Repair

Dear Colleagues,

Plenty of endogenous and exogenous accidents can engender DNA lesions, threatening genome integrity. These lesions, through the activation of signalling pathways, become rally points for proteins involved in DNA repair. Cells that are not able to cope with damaged DNA, or in which the required repair pathways are non-properly functional, undergo a series of events that increase genome instability and that, eventually, can lead to cancer or ageing. Moreover, most of the repair-generated intermediates are more toxic than the original lesion. Therefore, DNA repair is a critical process that needs to be tightly orchestrated, both temporally and spatially. In particular, shielding the DNA lesion from detection and processing by unwanted repair proteins, or the precise coordination of every enzymatic step, require protective mechanisms that can be achieved by compartmentalization, obtained by subdividing the soluble nuclear volume and generating a repair compartment around the DNA lesion.

These membraneless compartments can originate from liquid–liquid phase separation (LLPS), a demixing process that separates and concentrates cellular reactions contributing to the organization of the molecular events occurring within cells. LLPS largely depends on a network of protein–protein and protein–RNA transient interactions, primarily mediated by intrinsically disordered regions (IDRs) acting as the “sticky” portions of proteins. Recently, it has been demonstrated that noncoding RNAs can be synthetized at the DNA damage site and that several DNA repair enzymes are endowed with RNA binding and processing abilities that can potentially explain the assembling of membraneless structures around the foci of damage. More importantly, emerging evidence has associated dysfunctional LLPS events and neurodegeneration processes with the cellular response to DNA damage.

In this Special Issue, we want to highlight the latest insights in liquid–liquid phase separation involved in the DNA damage response (DDR), including but not limited to DDR protein unfolding events, interaction with RNAs, and new in vitro and in silico approaches for studying DDR-related phase partitioning. Furthermore, we want to shed light on a possible interplay between aberrant LLPS transition and DNA damage associated with neurodegeneration processes.

Dr. Gianluca Tell
Dr. Emiliano Dalla
Dr. Giulia Antoniali
Guest Editors

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• DNA Damage Response
• Base Excision Repair
• Liquid Liquid Phase Separation
• RNA binding proteins
• ncRNA
• Double-Strand Break repair