Exploring the G1 checkpoint's role in cell cycle regulation, this overview highlights how cells decide to divide or repair DNA. It delves into the functions of E2F transcription factors, retinoblastoma protein, and cyclin-CDK complexes in controlling cell division. The text also examines the mechanisms of cell cycle arrest and the transition to mitosis, including the G2 checkpoint and the concept of hysteresis in cell cycle transitions.
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The G1 checkpoint determines whether a cell will enter a resting state, repair DNA damage, or commit to cell division
Factors Influencing Decision
The cell's size, nutrient availability, growth factors, and genome integrity all play a role in the decision made at the G1 checkpoint
DNA Damage Response
DNA damage activates pathways that halt cell cycle progression, ensuring only cells with intact DNA replicate
The activation of specific cyclin-dependent kinases (CDKs) drives the transition from G1 to S phase, where DNA synthesis occurs
E2F transcription factors activate genes necessary for cell cycle progression, and dysregulation of their activity is often implicated in tumorigenesis
Rb Inhibition of E2F
Hypophosphorylated Rb inhibits E2F-mediated transcription, while phosphorylation by cyclin-CDK complexes releases E2F for gene activation
Phosphorylation of Rb
Phosphorylation of Rb by cyclin-CDK complexes during late G1 allows for the transcription of S phase genes
Cyclin/CDK Complex Activation
Growth factor signaling leads to the synthesis of cyclin D, which associates with CDK4 or CDK6 to initiate the phosphorylation of Rb and partial activation of E2F target genes
Full Activation of E2F
Subsequent binding of cyclin E to CDK2 leads to the full activation of E2F and transcription of genes that drive the cell into S phase
Cell Cycle Arrest
The kinase inhibitor p27^Kip1 binds to and inhibits cyclin E-CDK2 complexes, providing a brake on cell cycle progression
DNA Damage Response
In response to DNA damage, ATM and ATR kinases activate Chk1 and Chk2, which target Cdc25A for degradation, preventing the activation of cyclin E-CDK2 and arresting the cell cycle in G1
The G2 checkpoint ensures DNA integrity and synthesizes mitotic proteins in preparation for cell division
Checkpoint Mechanisms
ATR and ATM kinases can activate Chk1 and Chk2 to induce cell cycle arrest if DNA damage or replication errors are detected
Positive Feedback Loop
Plk1 kinase facilitates the activation of Cdc25 phosphatase and degradation of Wee1 kinase, promoting the entry into mitosis
The concept of hysteresis in cell cycle transitions, as described by the Novak-Tyson model, suggests that the threshold for activating mitotic entry is higher than that for maintaining mitosis
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G1 Checkpoint Function
Determines cell division commitment; integrates signals for repair, rest, or replication.
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Role of DNA Integrity in G1 Phase
Activates repair pathways; prevents cycle progression if damage detected.
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Transition from G1 to S Phase Mechanism
CDKs activation; initiates transcription for DNA replication genes.
