Short peptides (2-4 amino acid residues) inhibit or stimulate hydrolysis of λ phage DNA by eukaryotic endonucleases WEN1 and WEN2 depending on DNA methylation status. Peptide modulation of endonucleases activity most likely appears as a result of their binding to DNA. Peptides discriminate (recognize) not only certain DNA sequences, but also their methylation status. Apart from intact DNA, the test peptides bind to single-stranded DNA structures (oligonucleotides) containing NG- and CG-sites methylated in eukaryotes. Peptides affect the set of hydrolyzed sites during endonuclease hydrolysis of double-stranded structures. The effects of peptides with different primary structure on DNA hydrolysis by endonucleases are different and are modulated by histones (histone H1). Site-specific peptide interactions with DNA may epigenetically control genetic functions of the cell. These interactions probably played an important role at the very early stages of evolution.