ZIPPing the gaps: A new class of zinc finger proteins orchestrates the DNA damage response.

Maintaining genomic integrity is fundamental to cellular survival, the prevention of cancer and other pathologies. Central to this protective system is the DNA damage response (DDR), governed by an intricate cascade of post-translational modifications, among which poly(ADP-ribosylation) (PARylation) stands out for its rapid and spatially precise dynamics. Catalyzed by PARP1 and PARP2 at sites of DNA lesions, the resulting poly(ADP-ribose) (PAR) polymer functions as a signaling scaffold that drives repair factor recruitment, chromatin remodeling, and the seeding of liquid-liquid phase-separated repair condensates. This review synthesizes recent evidence to propose and define ZIPPs (Zinc finger proteins Interacting with PAR) as an emerging and functionally coherent class of DDR regulators. Although zinc finger proteins (ZFPs) have historically been associated with transcriptional regulation, a growing body of proteomic, biochemical, and cell biological evidence reveals that a large subset is directly recruited to DNA damage sites through non-covalent PAR interactions, a function entirely distinct from their canonical roles. We posit that this interaction is not merely incidental for the many ZIPPs discussed herein but reflects a dedicated functional relationship for at least a subset of these proteins, with specific ZIPPs possessing PAR-binding domains that enable them to act as readers of the PAR signal and translate it into precise downstream actions. The structural plasticity of zinc finger domains, spanning C2H2-type arrays, PBZ motifs, RING domains and other modules, enables ZIPPs to decode distinct PAR topologies in a temporally ordered fashion. We suggest viewing the DDR as two distinct phases each driven by separate waves of ZIPP activity. Within this framework, ZIPPs govern critical DDR decisions, including repair pathway choice, thereby functioning as essential coordinators rather than general contributors to genome stability. This perspective both challenges and refines current DDR models, and highlights ZIPPs as a promising new class of therapeutic targets for overcoming resistance to PARP inhibitor-based cancer therapies.