greatly ease its study. ''Learning how to unleash them [the ORC] in vitro could therefore reveal how this protein is regulated in vivo," say Li and Alberts.

In short, discovery of the multiprotein initiation factor in yeast provides a long sought after key for unlocking the secrets of the genomes of advanced organisms. For the past 40 years necessity often demanded that most research on the molecular details of DNA replication and expression be done on relatively simple, prokaryotic organisms. Now, a new era of biological studies could begin, one that puts more emphasis on the workings of the genome in advanced organisms, including humans.

EPILOGUE

Just as the discovery of the T antigen, dna A protein, and yeast origin recognition complex have yielded important clues about how DNA replication starts, the discovery of other proteins has revealed other details about the later stages of DNA replication. In most cases such information has been gained by analyses of mutant microbes that fail to replicate properly and are defective in a single protein. But the search can be very difficult since some proteins are only partially active in isolation and may have detectable activity only if found with large and, often elusive, protein complexes. Still, despite such difficulties, knowledge of the large number of proteins needed to complete DNA replication in E. coli is quite detailed, and there has been reasonable, but slow, progress in defining those proteins that have a role in the replication of eukaryotic DNA.

Here is a rundown of the key accessory proteins—sometimes called the protein machine—that help DNA to copy itself. Although the polypeptide components of the machinery may differ in detail from organism to organism, enough is known about them to conclude that some key polypeptides fill certain roles in DNA replication in all organisms. The proteins described here go into action after the initiator proteins described earlier.

Proteins That Keep Replication in Order

Once DNA is unraveled and replication begins, the active site of replication advances in both directions along the DNA strand until it meets an advancing replicating segment from a neighboring origin or the entire chromosome is copied. The spot where the newly synthesized



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