that includes the replicative polymerases is generally referred to as a holoenzyme. However, significant challenges remain: the leading and lagging strands are anti-parallel. This means that nucleotide synthesis on the leading strand naturally occurs in the 5' to 3' direction. However, the lagging strand runs in the opposite direction and this presents quite a challenge since no known replicative polymerases can synthesise DNA in the 3' to 5' direction. The dimerisation of the replicative polymerases solves the problems related to efficient synchronisation of leading and lagging strand synthesis at the replication fork, but the tight spatial-structural coupling of the replicative polymerases, while solving the difficult issue of synchronisation, creates another challenge: dimerisation of the replicative polymerases at the replication fork means that nucleotide synthesis for both strands must take place at the same spatial location, despite the fact that the lagging strand must be synthesised backwards relative to the leading strand. Lagging strand synthesis takes place after the helicase has unwound a sufficient quantity of the lagging strand, and this "sufficient quantity of the lagging strand" is polymerised in discrete nucleotide chains called Okazaki fragments. Consider the following: the helicase continuously unwinds the parental duplex, but the lagging strand must be polymerised in the opposite direction. This means that, while polymerisation of the leading strand proceeds, polymerisation of the lagging strand only occurs after enough of the lagging strand has been unwound by the helicase. At this point, the lagging strand replicative polymerase associates with the clamp and primer in order to start polymerisation. During lagging strand synthesis, the replicative polymerase sends the lagging strand back toward the replication fork. The replicative polymerase disassociates when it reaches an RNA primer. Helicase continues to unwind the parental duplex, the priming enzyme affixes another primer, and the replicative polymerase reassociates with the clamp and primer when a sufficient quantity of the lagging strand has unwound. Collectively, leading and lagging strand synthesis is referred to as being 'semidiscontinuous'. High-fidelity DNA replication Prokaryotic and eukaryotic organisms use a variety of replicative polymerases, some of which are well-characterised: DNA polymerase III DNA polymerase delta DNA polymerase epsilon DNA polymerase III This polymerase synthesizes leading and lagging strand DNA in bacteria. DNA polymerase delta This polymerase synthesizes lagging strand DNA in eukaryotes. (Thought to form an asymmetric dimer with DNA polymerase epsilon.) DNA polymerase epsilon This polymerase synthesizes leading strand DNA in eukaryotes. (Thought to form