DNA polymerase epsilon is essential for cell viability and chromosomal DNA replication in budding yeast. In addition, DNA polymerase epsilon may be involved in DNA repair and cell-cycle checkpoint control. The enzyme consists of at least four subunits in mammalian cells as well as in yeast. The largest subunit of DNA polymerase epsilon is responsible for polymerase activity. To date, the functions of the other subunits have remained unknown. With a view to elucidating the functions of the second largest subunit of mouse DNA polymerase epsilon (DPE2), yeast two-hybrid screening was performed to identify mouse proteins that interact with this subunit. SAP18, a polypeptide associated with co-repressor protein Sin3, was identified as an interacting protein. A part of the N-terminal region of DPE2 (comprising amino acids 85-250) was found to be responsible for the interaction with SAP18. The interaction induced repression of transcription in reporter plasmid assays, which was inhibited by trichostatin A. These results indicate that DPE2 may recruit histone deacetylase (HDAC) to the replication fork to modify the chromatin structure.