The nicks are finally sealed by DNA ligase 1 to complete Okazaki fragment processing. The flaps formed can be efficiently processed by the combined action of Flap endonuclease 1 (Fen1) and Dna2 to eventually create nicks. When Pol δ encounters a downstream Okazaki fragment, it displaces the 5’ end region of the Okazaki fragment, generating a single-stranded (ss) nucleic acid flap. The recognition of a primer RNA-DNA by the Replication-Factor C (RFC) complex leads to dissociation of Pol α-primase and loading of proliferating cell nuclear antigen (PCNA), resulting in recruitment of Pol δ to the primer-template junction, a process called ‘polymerase switching.’ Then the primer RNA-DNA is elongated by Pol δ. The synthesis of RNA portion (~ 10 to 15 ribonucleotides) and subsequent extension of short (~20 to 30 nucleotides, nt) DNA are coupled. Synthesis of an Okazaki fragment begins with a primer RNA-DNA made by polymerase (Pol) α-primase. Unlike leading strands, lagging strands are synthesized as discrete short DNA fragments, termed ‘Okazaki fragments’ which are later joined to form continuous duplex DNA. Leading strand synthesis, once initiated, occurs in a highly processive and continuous manner by a proofreading DNA polymerase. Activation of origins leads to the establishment of bidirectional replication forks for the DNA synthesis of leading and lagging strands. The assembly of replication initiation complex and its activation are well reviewed in many literatures ( Sclafani & Holzen, 2007 Remus & Diffley, 2009 Araki, 2010). The irreversible removal of initiation factors is a major mechanism to ensure DNA to be replicated once and only once per cell cycle. The elevated levels of Cdk activities lead to removal of some initiation proteins such as Cdc6 by proteolysis, allowing the pre-RC to be further activated for subsequent DNA synthesis.
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