Fork Reversal Safeguards Epigenetic Inheritance during DNA Replication Under Stress

During DNA replication, epigenetic information carried by histone modifications is faithfully propagated and re-established on sister chromatids, ensuring cell identity. DNA replication is tightly coupled to chromatin reassembly, therefore perturbations to DNA replication compromise epigenetic inheritance fidelity; however, the underlying mechanisms remain poorly understood. In this study, we reveal a critical role for replication fork reversal in maintaining the transmission of epigenetic information under replication stress. We show that cells defective in fork reversal exhibit reduced nucleosome density at replication forks, accompanied by the loss of parental histones during their transfer onto nascent DNA. Mechanistically, we showed that PrimPol activation leads to single-stranded DNA gaps in fork reversal deficient cells; PARylation and DNA–protein crosslinking on single-stranded DNA subsequently evicts nucleosomes. Our findings demonstrate that replication fork reversal, a widespread physiological process, is essential not only for preserving genome integrity but also for safeguarding epigenome stability.