# Fork Reversal Safeguards Epigenetic Inheritance During Replication Stress

## TL;DR

This study shows that replication fork reversal helps maintain epigenetic information during DNA replication stress, preventing loss of histones and ensuring genome stability.

## Contribution

The study identifies replication fork reversal as a novel mechanism for safeguarding epigenetic inheritance during replication stress.

## Key findings

- Cells lacking fork reversal show reduced nucleosome density and loss of parental histones at replication forks.
- PrimPol activation causes single-stranded DNA gaps, leading to PARylation and nucleosome loss in fork reversal-deficient cells.
- Replication fork reversal is essential for both genome and epigenetic stability under replication stress.

## Abstract

During DNA replication, epigenetic information carried by histone modifications is faithfully propagated and re-established on sister chromatids, ensuring cell identity. Chromatin reassembly is tightly coupled to DNA replication, however, whether and how perturbations to DNA replication affects the fidelity of epigenetic inheritance remain unclear. In this study, we reveal a critical role for replication fork reversal in maintaining the transmission of epigenetic information under replication stress. 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 demonstrate that PrimPol activation leads to single-stranded DNA gaps in fork reversal deficient cells, and that subsequent PARylation (poly ADP-ribosylation) and DNA–protein crosslinking on these gaps cause nucleosomes loss. Our findings demonstrate that replication fork reversal, a widespread physiological process, is not only essential for preserving genome integrity but also for safeguarding epigenetic stability.