From fork protection to chromatin compaction: Replication-associated determinants of PARP inhibitor response

PARP inhibitors (PARPi) exploit synthetic lethality to achieve durable responses in tumors with homologous recombination (HR) defects, most prominently BRCA1/2 deficiency. Yet resistance is common, and PARPi sensitivity varies widely across genetic and chromatin contexts. Although the replication fork protection (FP) model has been widely invoked, PARPi reduce reversed-fork accumulation, making nascent strand degradation (NSD) an unlikely primary driver of PARPi cytotoxicity. In contrast, a post-replicative single-stranded DNA gap (ssDNA gap) framework provides a more parsimonious explanation for PARPi sensitivity and the selective pressures that drive resistance. Building on this view, we propose an additional upstream structural variable— chromatin dynamics , encompassing local compaction state, nucleosome refill/reassembly, and remodeling plasticity—as a key modulator of whether gaps are buffered or amplified into lethal lesions. Importantly, PARPi response is not dictated by a single “open versus closed chromatin” axis: relaxed chromatin can promote toxic escalation by increasing structural volatility and conflict potential, whereas overly compact chromatin can also potentiate toxicity by masking lesions and restricting repair access. Thus, the relevant determinant is the capacity of chromatin to dynamically remodel and restore post-replicative chromatin integrity in the face of gap burden and PARP trapping. This gaps–chromatin framework offers a unifying conceptual coordinate system to interpret heterogeneous PARPi responses, nominate chromatin-linked biomarkers, and guide rational combination strategies.