Histone transcription and deposition are tightly regulated with the DNA replication cycle to maintain genetic integrity. Ams2 is a GATA-containing transcription factor responsible for core histone gene expression and for CENP-A loading at centromeres in fission yeast. Ams2 levels are cell cycle-regulated, and after the S phase Ams2 is degraded by the SCF(pof3) ubiquitin ligase; however, the regulation of Ams2 in G(1) or meiosis is poorly understood. Here we show that another ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C) targets Ams2 for destruction in G(1). Ubiquitylation and destruction of Ams2 is dependent upon a coactivator Cdh1/Ste9 and the KEN box in the C terminus of Ams2. We also find that stabilization of Ams2 sensitizes cells to the anti-microtubule drug thiabendazole and the histone deacetylase inhibitor tricostatin A when a histone deacetylase gene hst4 is deleted, suggesting that histone acetylation together with Ams2 stability ensures the coupling of mitosis to DNA replication. Furthermore, in meiosis, the failure of the APC/C-mediated destruction of Ams2 is deleterious, and pre-meiotic DNA replication is barely completed. These data suggest that Ams2 destruction via both the APC/C and the SCF ubiquitin ligases underlies the coordination of histone expression and DNA replication.