G1/S Checkpoint Regulation of the Cell Cycle
The G1/S checkpoint is a critical regulatory point in the cell cycle that ensures a cell is prepared to enter S phase and begin DNA replication. This checkpoint monitors for DNA damage, sufficient cell size and adequate nutrient availability, halting progression if conditions are not optimal. By enforcing a pause in the cycle, the G1/S checkpoint allows time for repair of damaged DNA and is essential for maintaining genomic integrity.
Pathway Summary
In Eukaryotic cells, cell cycle checkpoint regulation ensures the fidelity of cell division. This kind of control verifies whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase. Mitogen-dependent progression through the first gap phase (G1) of the mammalian cell-division cycle is precisely regulated so that normal cell division is synchronous with cell growth. Also, the initiation of DNA synthesis (S phase) has to be timed precisely to avoid inappropriate DNA amplification which can result in genomic instability. The G1/S cell cycle checkpoint controls the passage of eukaryotic cells from the G1 into the S phase.The key components involved in the G1/S checkpoint are the cell cycle kinases, CDK4/6-cyclin D and CDK2-cyclin E, and the transcription complex that includes the retinoblastoma protein (Rb) and transcription factor E2F. The retinoblastoma protein is a nuclear phosphoprotein that regulates growth in the G1 phase of the cell cycle. Hypophosphorylated Rb exerts its growth-inhibitory effects by inhibiting critical regulatory proteins like E2F. The activation of E2F is necessary for the G1-S transition. Phosphorylation of Rb by CDK4/6-cyclin D and CDK2-cyclin E appears to release E2F and another trans factor DP-1 from an inhibitory complex, enabling them to promote the transcription necessary for progression into late G1 and S phase.Several stimuli exert check point control. These include transforming growth factor β (TGFβ), DNA damage, UV stress, replicative senescence, growth factor withdrawal and contact inhibition. Check point control largely involves the phosphorylation and inhibition of CDK4/6 and CDK2 by the INK4 and Cip/Kip family of cell cycle kinase inhibitors. TGFβ exerts additional checkpoint control by repressing the transcription of the phosphatase CDC25, which is an activator of cell cycle kinases. Growth factor removal activates Glycogen synthase kinase β (GSKβ), which in turn phosphorylates Cyclin D and marks it for ubiquitination. Ubiquitination and degradation of cyclins D and E by the Skp, Cullin, F-box containing complex (SCF complex) is another mechanism of checkpoint control.The G1/S checkpoint control is vital in normal cell division Mutations in the check point proteins can lead to apoptosis or tumorigenesis. This pathway highlights the key components of the G1/S checkpoint regulation.
Cell Cycle: G1/S Checkpoint Regulation Genes list
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Products related to Cell Cycle: G1/S Checkpoint Regulation
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Overview of G1/S checkpoint regulation
G1 phase of the cell cycle occurs immediately after mitosis and before DNA synthesis (S phase). During the G1 (Gap 1) cell phase, the cell grows in size, produces RNA and proteins necessary for DNA replication and prepares for entry into S phase. At the end of G1 cell phase, the G1/S checkpoint acts as a control mechanism. It assesses whether the cell is ready to make a commitment to DNA replication and division or whether it needs to pause and/or abandon the process.
The G1/S checkpoint monitors several key cellular conditions to ensure the success of cell division and safeguard against premature or inappropriate cell cycle progression. At a basic level, the checkpoint assesses cell size, ensuring the cell has grown enough to support two new daughter cells after mitosis. It also evaluates whether the cell has sufficient nutrients and energy reserves available to support DNA synthesis and mitosis.
With these criteria met, the G1/S checkpoint verifies the presence of external cues that provide the signal for progression and assesses DNA integrity – checking for the presence of DNA damage. If no DNA damage is detected and all other signals concur that the cell is healthy, the cell will be allowed to move into S phase. If DNA damage is detected, the cell cycle process will be paused, allowing for repairs to be completed before resuming. If the DNA damage is too severe, apoptosis may be triggered.
G1/S checkpoint assessment of DNA damage and repair
DNA damage is the major inhibitor of S phase entry. The G1/S checkpoint process actively monitors the integrity of the cell’s DNA, initiating a checkpoint signaling cascade that pauses cell cycle progression when DNA damage is detected. The process, which shares many components with the G2/M checkpoint later in the cell cycle, is generally broken into four steps: sensing DNA damage, activating checkpoint kinases, cell cycle arrest and finally, resolution and resumption of the cell cycle.
DNA damage sensing: ATM and ATR kinases
As with the G2/M checkpoint response later in the cell cycle, the DNA damage response begins with activation of the phosphatidylinositol 3-kinase–like kinases (PIKKs), ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad3-related). ATM is primarily activated by double-strand breaks and is recruited to the damaged site via the MRN complex. ATR responds mainly to single stranded DNA (ssDNA) lesions and is recruited with help from the ATRIP protein and RPA-coated ssDNA.
Cell cycle checkpoints kinase activation and p53 signaling
Once again, similar to the G2M/S checkpoint response, ATM and ATR phosphorylate downstream effector kinases CHK1 and CHK2. At the G1/S phase checkpoint, these kinases contribute to stabilizing and activating p53, the central tumor suppressor protein, by preventing its degradation by MDM2. Activated p53 protein acts as a transcription factor that upregulates the expression of p21, a cyclin-dependent kinase inhibitor.
Cell cycle arrest: p21 and Cyclin E/CDK2 inhibition
Cyclin-dependent kinase (CDK) activity is a key driver of the transition from G1 to S phase. p21 directly binds and inhibits the Cyclin E/CDK2 complex. When Cyclin E/CDK2 is inhibited, it can no longer phosphorylate the Rb (retinoblastoma) protein. Unphosphorylated (active) Rb continues to bind and inhibit E2F transcription factors, thereby blocking transcription of replication machinery genes.
Resolution and progression to DNA synthesis
Once the DNA damage is repaired, ATM and ATR signaling is diminished, p53 levels decline and p21 is degraded. This relieves inhibition of Cyclin E/CDK2, allowing it to phosphorylate Rb. Phosphorylated Rb releases E2F transcription factors, which then activate genes necessary for S-phase entry and DNA synthesis. Passage through the restriction point commits the cell to S phase, regardless of subsequent extracellular conditions, ensuring orderly progression.
This checkpoint pathway acts as a safeguard, ensuring that only genetically stable cells proceed to DNA replication. Disruption in any part of this pathway, particularly loss of p53 function or deregulation of Cyclin/CDK activity can bypass the checkpoint entirely, allowing cells to replicate damaged DNA – a key hallmark of cancer.
Consequences of defective G1/S checkpoint regulation
Defective regulation of the G1 phase checkpoint has significant consequences for cellular integrity and cancer development. Mutations in several tumor suppressors such as p53, Rb, Cyclin D, CDK4/6 or p21 frequently disrupt this checkpoint in human cancers. When the checkpoint fails to properly detect or respond to DNA damage, cells proceed into S phase with unrepaired lesions, leading to the accumulation of mutations and genomic instability. Over time, this instability leads to tumorigenesis by enabling the activation of oncogenes and loss of tumor suppressors.
Additionally, impaired checkpoint control disrupts normal cell cycle exit mechanisms, allowing for uncontrolled cell proliferation. This unchecked growth is a hallmark of malignant transformation.
Moreover, many cancer therapies, such as radiation and DNA-damaging chemotherapeutics, rely on intact checkpoint responses to induce cell cycle arrest or apoptosis. In cells with defective G1 checkpoint machinery, especially those with p53 mutations, this damage response is compromised, contributing to resistance to therapy and making treatment less effective.
References
- Hume S, Dianov GL, Ramadan K. A unified model for the G1/S cell cycle transition. Nucleic Acids Res. 2020;48(22):12483–12501.
- Zhang H, Xu J, Long Y, Maimaitijiang A, Su Z, et al. Unraveling the guardian: p53's multifaceted role in the DNA damage response and tumor treatment strategies. Int J Mol Sci. 2024;25(23):12928.