Nucleotide supply, not local histone acetylation, sets replication origin usage in transcribed regions

Area of Science:

• Molecular Biology
• Cell Biology
• Genetics

Background:

• DNA replication origin firing is regulated, with histone acetylation proposed as a key factor.
• Previous studies yielded conflicting results regarding the role of histone acetylation in origin efficiency.

Purpose of the Study:

• To investigate the relationship between local histone acetylation and DNA replication origin firing efficiency.
• To reconcile conflicting findings on histone acetylation's role in origin control.

Main Methods:

• Analysis of origin efficiencies and histone acetylation at the adenosine monophosphate deaminase 2 locus in mammalian fibroblasts.
• Treatment with a deacetylase inhibitor and assessment of its effects on replication initiation patterns, pyrimidine biosynthesis, and replication fork speed.

Main Results:

• Local histone acetylation levels did not correlate with origin firing efficiencies.
• Modulating origin efficiency did not impact histone acetylation.
• Deacetylase inhibitor treatment altered replication initiation patterns, affected pyrimidine biosynthesis, and reduced replication fork speed.
• Reduced fork speed led to the recruitment of latent origins.

Conclusions:

• Histone acetylation is not a direct determinant of replication origin firing efficiency at the studied locus.
• Deacetylase inhibitors influence replication dynamics through mechanisms independent of direct acetylation control of origin firing.
• The findings clarify previously inconsistent results and highlight an unexpected role for deacetylase inhibitors in DNA replication.