The origin recognition complex (ORC) in eukaryotes was first discovered in Saccharomyces cerevisiae by Stephen P. Bell and Bruce Stillman. Information from previous studies had shown that autonomous replication sequences (ARS) in the chromosome are the origins of replication (Bell 1992). Studies also showed that an 11-base-pair sequence called the ARS core consensus sequence (ACS) is conserved along all ARS elements and is required for ARS function. However, no study had been able to identify a protein that recognized the double-stranded form of the ACS until the DNA-binding activity of the ORC was discovered (Bell 1992).
Bell and Stillman discovered the ORC DNA-binding activity when they conducted a fractionation of nuclear protein ABF1 that resulted from DNA binding studies on crude yeast nuclear extract and ARS1 DNA (Bell 1992). The fractionation showed that ORC protected the A and B1 elements of ARS1 from deoxyribonuclease I digestion. They were able to purify the DNA-binding activity through conventional and DNA-affinity chromatography. It was then discovered after fractionation of the binding activity by glycerol gradient sedimentation and SDS-polyacrylamide gel analysis of the purified activity that there was a multiprotein complex responsible for the origin binding activity. Footprinting assays with DNA fragments containing ARS1 sequences then showed that increasing concentrations of ORC protein resulted in more protection of the elements A, B1, B2, and B3 (Bell 1992).