Fork Reversal Safeguards Epigenetic Inheritance During Replication Stress.

Area of Science:

• Molecular Biology
• Epigenetics
• Genomics

Background:

• Epigenetic information, carried by histone modifications, is vital for cell identity and is normally propagated during DNA replication.
• The impact of DNA replication perturbations on epigenetic inheritance fidelity remains largely unknown.

Purpose of the Study:

• To investigate the role of replication fork reversal in maintaining epigenetic information transmission under replication stress.
• To elucidate the molecular mechanisms by which replication fork defects affect epigenetic stability.

Main Methods:

• Analysis of nucleosome density at replication forks in cells with and without fork reversal.
• Tracking of parental histone transfer onto nascent DNA.
• Investigating the role of PrimPol, PARylation, and DNA-protein crosslinking in fork reversal-deficient cells.

Main Results:

• Cells defective in replication fork reversal show reduced nucleosome density and loss of parental histones at replication forks.
• PrimPol activation in these cells leads to single-stranded DNA gaps.
• PARylation and DNA-protein crosslinking on these gaps contribute to nucleosome loss.

Conclusions:

• Replication fork reversal is essential for the faithful transmission of epigenetic information during DNA replication stress.
• This process safeguards both genome integrity and epigenetic stability, ensuring cell identity.