Orc

the synthesis of SV40 DNA (see Figure 4-34); these proteins are required for continued synthesis of the leading strand and for synthesis of most of the lagging strand. An additional DNA polymerase, Pol e, is also required for chromosomal DNA synthesis, but its function is not yet understood.

As the replication forks progress away from each origin, presumably phosphorylated forms of Cdc6, Cdt1, and Mcm10 are displaced from the chromatin. However, ORC complexes immediately bind to the origin sequence in the replicated daughter duplex DNAs and remain bound throughout the cell cycle (see Figure 21-26, step 4). Origins can fire only once during the S phase because the phosphorylated initiation factors cannot reassemble into a pre-replication complex. Consequently, phosphorylation of components of the pre-replication complex by S-phase cyclin-CDK complexes and the DDK complex simultaneously activates initiation of DNA replication at an origin and inhibits re-initiation of replication at that origin. As we have noted, B-type cyclin-CDK complexes remain active throughout the S phase, G2, and early anaphase, maintaining the phosphorylated state of the replication initiation factors that prevents the assembly of new pre-replication complexes (step 5).

Only when the APC triggers degradation of all B-type cyclins in late anaphase and telophase does the then unopposed action of phosphatases remove the phosphates on the initiation factors (Cdc6, Cdt1, and Mcm10), allowing the reassembly of pre-replication complexes during G1. As discussed previously, the inhibition of APC activity throughout G1 sets the stage for accumulation of the S-phase cyclins needed for onset of the S phase. This regulatory mechanism has two consequences: (1) pre-replication complexes are assembled only during G1, when the activity of B-type cyclin-CDK complexes is low, and (2) each origin initiates replication one time only during the S phase, when S phase cyclin-CDK complex activity is high. As a result, chromosomal DNA is replicated only one time each cell cycle.

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