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Regulating Replication

DNA replication must be tightly coordinated with cell division, so that extra copies of chromosomes are not created and each daughter cell receives exactly the right number of each chromosome. DNA replication is regulated by DNA replication proteins.

Function(s) Bacteria Eukaryotes
single-stranded DNA binding, SSB (one subunit) RPA (three subunits)
stimulates DNA polymerase, promotes origin unwinding
clamp loader γδ/δ′τ (5 subunits) RFC (five subunits)
sliding clamp, holds DNA β (two identical subunits) PCNA (three identical subunits)
polymerase on DNA
replicative DNA polymerase, DNA polymerase III DNA polymerase δ (two subunits)
proofreading exonuclease DNA polymerase ε (four subunits)
DNA primase DnaG DNA polymerase α (four subunits)
Okazaki fragment processing DNA polymerase I Dna2
RNase FEN1
DNA ligase H RNase H
DNA ligase I
DNA helicase DnaB ?
Swivel ahead of ω Topoisomerase I
replication fork DNA gyrase Topoisomerase II
Initiator protein DnaA Origin Recognition Complex (six subunits)

controlling the assembly of complexes at replication origins. In bacteria, the accumulation of the initiator protein, dnaA, seems to be an important factor in determining when replication begins.

In eukaryotes, DNA replication and cell division are separated by two "gap" cell cycle phases (G1 and G2), during which neither DNA replication nor nuclear division occurs. DNA replication occurs during the S (or synthesis) phase, but ORC is thought to bind replication origins throughout the cell cycle. During the G1 phase of the cell cycle, ORC helps to assemble other replication initiation factors at replication origins to make so-called pre-replicative-complexes (pre-RCs) that are competent to initiate replication during S phase. These other initiation factors include a protein called Cdc6 and a family of six related MCM ("mini-chromosome maintenance") proteins. The functions of these proteins are not yet known; however, the MCM proteins are currently the best candidate for the eukaryotic replicative helicase, and Cdc6 is necessary for MCM proteins to bind DNA. DNA polymerase also assembles on origins during this time.

Replication initiation is actually triggered at the beginning of S phase by the phosphorylation (addition of a phosphate group to) of one or more proteins in the pre-RC. The enzymes that phosphorylate proteins in the pre-RC are called protein kinases. Once they become active, they not only trigger replication initiation, but they also prevent the assembly of new pre-RCs. Therefore, replication cannot begin again until cells have completed cell division and entered G1 phase again.

Carol S. Newlon


Baker, T. A., and S. P. Bell. "Polymerases and the Replisome: Machines within Machines." Cell 92 (1998): 295-305.

Cooper, Geoffrey M. The Cell: A Molecular Approach. Washington, DC: ASM Press, 1997.

Herendeen, D. R., and T. J. Kelly. "DNA Polymerase III: Running Rings Around the Fork." Cell 84 (1996): 5-8.

Lodish, Harvey, et al. Molecular Cell Biology, 4th ed. New York: W. H. Freeman, 2000.

Stillman, B. "Cell Cycle Control of DNA Replication." Science 274 (1996): 1659-1664.

Internet Resource

Davey, M., and M. O'Donnell. "DNA Replication." Genome Knowledge Base Website. <http://gkb.cshl.org/db/index>.

Inhibitors of viral helicaseprimase enzymes are being tested as a new treatment for herpes virus infection.

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 4Replication - Overview, Initiation Of Dna Replication, The Replication Fork, Leading Strands And Lagging Strands, The Need For Primers