G1-S Phase Transition
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G1-S Phase Transition
Cell cycle arrest in response to DNA damage is an important mechanism for maintaining genomic integrity. This cell cycle arrest provides time for DNA repair to prevent replication or segregation of damaged DNA. Induction of growth arrest by DNA damage occurs mainly through the activation of checkpoint pathways that delay cell cycle progression at G1, S, and G2 (Ref.1).

In vertebrate cells, the commitment to complete a round of mitotic division takes place during the initial phase of the cell cycle (G1), at a stage called the restriction (R) point, preceding the onset of DNA synthesis (S-phase) (Ref.2). Two cell cycle kinases, CDK4/6 (Cyclin-Dependent Kinase)-Cyclin-D and CDK2-Cyclin-E,and the transcription complex that includes Rb (Retinoblastoma)-family proteins (also called "pocket proteins") and E2F are pivotal in controlling this checkpoint. pRb-family proteins are negative growth-regulators in their active form. During G1-phase, the Rb-HDAC (Histone Deacetylases) repressor complex binds to the E2F-DP1 transcription factors, inhibiting the downstream transcription. Five E2F proteins (E2F-1 to 5) and three DP proteins (DP-1, DP-2 and DP-3) have been cloned. Heterodimerization between E2F and DP is required for efficient DNA binding, transcriptional activity, and binding to pocket proteins.E2F1, E2F2 and E2F3 bind predominantly pRb, E2F4 binds all known pocket proteins and E2F5 binds predominantly p130 (Ref.3). Phosphorylation of Rb by CDK4/6 and CDK2 dissociates the Rb-repressor complex, permitting transcription of S-phase genes encoding for proteins that amplify the G1 to S-phase switch that is required for DNA replication. There are several proteins that can inhibit the cell cycle in G1. If DNA damage has occurred, p53 accumulates in the cell and induces the p21(CIP1)-mediated inhibition of Cyclin-D/CDK (Ref.4). If the Cyclin-D/CDK complex is inhibited, Rb protein is in a state of low phosphorylation and is tightly bound to the transcription factor E2F , inhibiting its activity. Cyclin-E/CDK2 accumulates during late G-phase and triggers the passage into S-phase. The entire genome is replicated during S-phase. The synthesis and accumulation of Cyclin-B/CDC2 also begins during S-phase, but the complex is phosphorylated at Thr14 -Tyr15 and is inactive. Many different stimuli also exert checkpoint control including TGF-Beta , DNA damage, contact inhibition, replicative senescence, and growth factor withdrawal. The first four act by inducing members of the INK4 ( p16INK4A , p15(INK4B), p18(INK4C) and p19(INK4D)) or KIP/CIP (p21(CIP1), p27(KIP1) and p57KIP2) families of cell cycle kinase inhibitors (Ref.5). Activation of TGF-Beta receptors also induces the inhibition of Cyclin-D/CDK by p15, while cAMP (cyclic Adenosine 3, 5’-Monophosphate) inhibits the Cyclin-D/CDK complex via p27. TGF-Beta additionally inhibits the transcription of CDC25A, a phosphatase that activates the cell cycle kinases. Growth Factor withdrawal activates GSK3Beta (Glycogen Synthase Kinase-3), which phosphorylates Cyclin-D, leading to its rapid ubiquitination and proteosomal degradation. Ubiquitination, nuclear export, and degradation are mechanisms commonly used to rapidly reduce the concentration of cell cycle control proteins.

The balance between cell differentiation and proliferation is regulated at the transcriptional level and in the cell cycle the transition from G1 to S-phase (G1/S transition) is of paramount importance in this regard. It is only before this point that cells can be oriented toward the differentiation pathway beyond which the cells progress into the cycle in an autonomous manner.