Initiation and Termination Mechanism of S phase

DNA replication occurs in the S phase of the cell cycle.  As mentioned in Chapter 7 Section A, DNA replication is triggered by the expression of all required proteins.  In mammals, the expression of these necessary proteins is activated by the transcription factor E2F  which, in turn, is regulated by the protein pRB (the protein product of the retinoblastoma gene).  When pRB binds to E2F, it will inactivate the transcriptional function of E2F, thereby inhibiting DNA replication.  With such a critical role, pRB is known as the "master brake of cell division".

Figure 8-A-4.  The Initiation and termination process of the S phase.
During G₀ or early G₁ phase, E2F is inactivated by pRB.  In late G₁ phase, the Cyclin D-Cdk4 complex phosphorylates a specific set of sites on pRB, resulting in the release of E2F, which then leads to the production of proteins needed for DNA replication.  E2F also stimulates the production of Cyclin E, cyclin A and E2F itself.  The Cyclin E-Cdk2 complex can also phosphorylate pRB, thus accelerating the cell cycle advance into the S phase.  On the other hand, the Cyclin A-Cdk2 complex can phosphorylate E2F, abolishing its transcriptional function.  Consequently, DNA replication is terminated.
It is interesting to note that the Cyclin E-Cdk2 complex cannot phosphorylate E2F.  Otherwise, the DNA replication would be terminated prematurely.

Review Articles:

The E2F family: specific functions and overlapping interests - EMBO J., 2004.

Evolving intricacies and implications of E2F1 regulation - FASEB J., 2003.

Signaling Networks That Link Cell Proliferation and Cell Fate - J. Biol. Chem., 2002.

The Rb/E2F pathway: expanding roles and emerging paradigms - Genes and Development, 2000.

The regulation of E2F by pRB-family proteins - Genes and Development, 1998.