In contrast to current dsDNA detection methods, retention of the native structure is possible by utilizing transcription factors to recognize their respective target nucleotide sequences. Dissected signal proteins that are initially non-functional are attached to DNA binding domains. A functional interaction that produces an observable signal is achieved when the dissected proteins are brought into proximity due to DNA recognition. This novel DNA detection method is designated SEquence-Enabled Reassembly (SEER). In a continuing effort to optimize the sensitivity of a SEER-GFP system that employs dissected Green Fluorescent Protein (GFP) as the signaling domain, we have considered two additional GFP variants: the Enhanced Green Fluorescent Protein (EGFP) and Venus. Of the three signaling domains, Venus conferred the highest sensitivity to the system. Future endeavors will involve the development of a mCpG-SEER-Venus system that is capable of site specific evaluation of methyl-CpG (mCpG) islands through the use of a methyl-CpG binding domain.