Nucleotide supply, not local histone acetylation, sets replication origin usage in transcribed regions.
In eukaryotes, only a fraction of replication origins fire at each S phase. Local histone acetylation was proposed to control firing efficiency of origins, but conflicting results were obtained. We report that local histone acetylation does not reflect origin efficiencies along the adenosine monophosphate deaminase 2 locus in mammalian fibroblasts. Reciprocally, modulation of origin efficiency does not affect acetylation. However, treatment with a deacetylase inhibitor changes the initiation pattern. We demonstrate that this treatment alters pyrimidine biosynthesis and decreases fork speed, which recruits latent origins. Our findings reconcile results that seemed inconsistent and reveal an unsuspected effect of deacetylase inhibitors on replication dynamics.
Gay
Sophie
S
Institut Curie, Centre de Recherche, 26 rue d'Ulm, 75248 Paris, France.
Lachages
Anne-Marie
AM
Millot
Gael A
GA
Courbet
Sylvain
S
Letessier
Anne
A
Debatisse
Michelle
M
Brison
Olivier
O
D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D004261:DNA Replication; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D056572:Histone Deacetylase Inhibitors / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000378:metabolism; D009711:Nucleotides / Q000378:metabolism*; D018741:Replication Origin; D014158:Transcription, Genetic
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009711:Nucleotides; C012589:trichostatin A; D006655:Histone Deacetylases