DNA replication is tightly controlled by histone-modifying enzymes. In the ciliate Tetrahymena, knockout of histone methyltransferase TXR1 (TXR1 KO), specific for H3 lysine 27 mono-methylation (H3K27me1), leads to severe replication stress and DNA damage response. Here we investigate the mechanism by which DNA replication is regulated by TXR1. We demonstrate a cell cycle-dependent oscillation of TXR1 at mRNA and—more strikingly—protein levels. TXR1 peaks in G1 phase but is quickly depleted upon entering S phase. Correspondingly, H3K27me1 is built up slowly in newly synthesized histones, showing a much higher level in G1 phase than G2 phase. TXR1 degradation in S phase is most likely mediated by PCNA, as point mutations at the PCNA-interacting protein (PIP) motif cause TXR1 to accumulate at S phase. Strains with TXR1 PIP mutations as well as TXR1 overexpression show replication defects, which are distinct from the TXR1 KO phenotype. We therefore conclude that cell cycle control of TXR1 levels ensures proper DNA replication in Tetrahymena.