We have isolated and sequenced a mouse replacement variant histone H3.3 cDNA. It corresponds to the most abundant mRNA expressed from a unique gene by the use of one out of three polyadenylation sites. The 3′ non coding region of H3.3 is very long ( ∼ 1100 nt) and highly conserved throughout evolution since it is about 95% homologous to the 3′ non coding region of the chicken H3.3B gene (1). We studied the expression of the H3.3 gene during SV40- and polyoma-induced mitotic host reaction in confluent, Go-arrested primary mouse kidney cell cultures. H3.3 replacement variant mRNA steady state levels increased during the Go to S-phase transition, apparently as the result of two mechanisms: one related to cell growth, whereas the other was linked to cellular DNA synthesis. The latter mechanism was however far less pronounced than with replication histone variant mRNAs. The bioloaical imvlications of these results are discussed.