Processivity factors

Abstract

What are they? The processivity factors PCNA and β are ring-shaped proteins that are essential for the movement of DNA polymerases in chromosome replication. Also known as … DNA sliding clamps, because they slide freely on DNA. But among the more imaginative names used to describe them, the most gustative are ‘doughnut’ and ‘bagel’. Less tasty names include torus, ring, washer, curtain rod, mobile platform and tracking protein. How do they work? They encircle duplex DNA and act as a mobile tether by binding to the DNA polymerase, holding it to DNA and making it behave in a highly ‘processive’ fashion. What is processivity? A protein is said to be processive if it catalyzes numerous catalytic turnover events while remaining with its substrate. Most single-subunit DNA polymerases only stay on DNA for a few nucleotide additions but, with the help of processivity factors, they can stay there for thousands of nucleotide addition steps. Processivity is especially important for the replication of long chromosomes. How do they get onto DNA? They can't do it by themselves. Another factor, a ‘clamp loader’, is needed to couple ATP hydrolysis to the opening and closing of these rings around DNA. Where are they found? PCNA (proliferating cell nuclear antigen) is the sliding clamp of eukaryotes, from yeast to humans. As its name implies, PCNA is associated with the proliferating state. The β subunit is the sliding clamp of prokaryotes. They first came to prominence … In 1993, when the crystal structure of the Escherichia coli β subunit was solved. The beautiful symmetrical structure speaks volumes for its function and displaced the structure of tRNA from the cover of Nucleic Acids Research, where it had been for too many years. PCNA and β have very similar structures (see Figure 1). Who are their known associates? PCNA works with two DNA polymerases, δ and ϵ. (The cell cycle kinase inhibitor p21 blocks the interaction between PCNA and DNA polymerase δ.) It's not known whether DNA polymerase ϵ acts with PCNA for replication or for repair. PCNA also binds to several other types of protein — such as DNA ligase I, FenI exonuclease and a DNA methyltransferase — but it's not clear why. The β clamp functions with DNA polymerase III and DNA polymerase II. What else do they do? PCNA and β are also involved in mismatch repair, and in eukaryotic excision repair. Most likely to be mentioned by … Jerard Hurwitz, Bruce Stillman, Tom Kelly, Peter von Hippel, Kenneth Marians, Charles McHenry and, of course, this author. Do they have commercial potential? Yes. The β factor of bacteria might be an attractive target for an antibacterial compound to shut down chromosome replication. The need for PCNA in replication and repair, and its association with the proliferative state, suggest it might be an important target for future cancer therapy. Don't say … “DNA polymerase I is highly processive.” It only extends DNA for 1–50 nucleotides and therefore is only slightly processive. Do say … “The β clamp makes DNA polymerase III the fastest and most processive polymerase in the world.” M O’Donnell, Howard Hughes Medical Institute, The Rockefeller University, 1230 York Avenue, New York 10021, USA.