Emerging connections: Poly(ADP-ribose), FET proteins and RNA in the regulation of DNA damage condensates

Our genome is exposed to thousands of DNA lesions every day, posing a significant threat to cellular viability. To deal with these lesions, cells have evolved sophisticated repair mechanisms collectively known as the DNA damage response. DNA double-strand breaks (DSBs) are very cytotoxic damages, and their repair requires the precise and coordinated recruitment of multiple repair factors to form nuclear foci. Recent research highlighted that these repair structures behave as biomolecular condensates, i.e. membraneless compartments with liquid-like properties. The formation of condensates is driven by weak, multivalent interactions among proteins and nucleic acids, and recent studies highlighted the roles of poly(ADP-ribose) (PAR) and RNA in regulating DSBs-related condensates. Additionally, the FET family of RNA-binding proteins (including FUS, EWS and TAF15), has emerged as a critical player in the DNA damage response, with recent evidence suggesting that FET proteins support the formation and dynamics of repair condensates. Notably, phase separation of FET proteins is implicated also in their pathological functions in cancer biology, highlighting the pervasive role of condensation. This review will provide an overview of biomolecular condensates at DSBs, focusing on the interplay among PAR and RNA in the spatiotemporal regulation of FET proteins at repair complexes. We will also discuss the role of FET condensates in cancer biology and how they are targeted for therapeutic purposes. The study of biomolecular condensates holds great promise for advancing our understanding of key cellular processes and developing novel therapeutic strategies, but requires careful consideration of potential challenges.