CR/periphilin (CR) retards cell cycle progression mainly at the S-phase in part by transcriptionally repressing expression of Cdc7, the key regulator of DNA replication, and in part by unknown mechanisms. In this study, we show that enforced expression of CR inhibits Cdc7 promoter activity. The attachment of the DNA-binding domain of the yeast GAL4 transcription factor to CR that appears without DNA-binding sequences, enables CR to repress GAL4 promoter-mediated transcription in a histone deacetylase (HDAC) activity-dependent manner. CR forms a complex with mSin3A, a common component in transcriptional repressor complexes, as well as with HDAC1, suggesting that CR may behave as a co-repressor by functional interaction with the Sin3/HDAC co-repressor complex. We also demonstrate that an alternatively spliced variant of CR, CR-S, which is without a region encoded by exon 4 of the CR gene and is a weak interactor with HDAC1, shows a suppressing effect on CR activity. (C) 2007 Elsevier Inc. All rights reserved.