Replication of minichromosomes in Saccharomyces cerevisiae is sensitive to histone gene copy number and strain ploidy.

We have characterized a defect in the mitotic transmission of plasmid minichromosomes in yeast strains deleted for the more highly expressed pair of histone H3 and H4 genes. Several observations indicate that an impairment in DNA replication contributes to the decrease in minichromosome stability. First, the maintenance of ARS plasmids that lack centromeres was also defective. Second, the addition of multiple ARS elements suppressed the defect in plasmid maintenance. Third, a synergistic increase in plasmid loss rate was seen when a plasmid containing an inefficient mutated ARS was tested in a strain deleted for histone genes, implying an interaction between ARS activity and the histone gene deletion. These results support the existence of a histone-dependent step in the initiation of DNA replication. We find that the stability of native chromosomes is not affected in strains deleted for histone genes. We propose that reduced histone H3 and H4 protein decreases the efficiency of initiation at ARS elements on plasmids and chromosomes, but that the presence of multiple origins on chromosomes compensates for the reduced efficiency. We find that decreased minichromosome stability is suppressed by increases in strain ploidy. The greater stability due to ploidy increases is not due to a relative increase in the expression of histone genes. We discuss models for the effect of strain ploidy on minichromosome maintenance.