Lombardi Silvia, Zilocchi Mara, Nicsanu Roland, Barabino Silvia Maria Luisa
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, Milano 20126, Italy.
DNA Repair (Amst). 2025 Jun;150:103846. doi: 10.1016/j.dnarep.2025.103846. Epub 2025 May 8.
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.
我们的基因组每天都会遭受数以千计的DNA损伤，这对细胞的生存能力构成了重大威胁。为了应对这些损伤，细胞进化出了复杂的修复机制，统称为DNA损伤反应。DNA双链断裂（DSBs）是极具细胞毒性的损伤，其修复需要精确且协调地招募多种修复因子以形成核灶。最近的研究强调，这些修复结构表现为生物分子凝聚物，即具有类液体性质的无膜区室。凝聚物的形成由蛋白质和核酸之间的弱多价相互作用驱动，最近的研究突出了聚（ADP - 核糖）（PAR）和RNA在调节与DSBs相关的凝聚物中的作用。此外，RNA结合蛋白的FET家族（包括FUS、EWS和TAF15）已成为DNA损伤反应中的关键参与者，最近有证据表明FET蛋白支持修复凝聚物的形成和动态变化。值得注意的是，FET蛋白的相分离也涉及其在癌症生物学中的病理功能，凸显了凝聚作用的普遍作用。本综述将概述DSBs处的生物分子凝聚物，重点关注PAR和RNA在修复复合物中FET蛋白的时空调节中的相互作用。我们还将讨论FET凝聚物在癌症生物学中的作用以及它们如何被用于治疗目的。生物分子凝聚物的研究对于增进我们对关键细胞过程的理解和开发新的治疗策略具有巨大潜力，但需要仔细考虑潜在的挑战。
