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What is the consequence of p53 mutations in response to DNA damage?
What is the role of ATM in response to DNA damage?
What is the consequence of severe DNA damage that cannot be repaired?
What is the role of Anaphase-promoting complex (APC) in mitosis?
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What is the role of SCF in the cell cycle?
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What is the consequence of loss of p53 function in cancer cells?
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What is the role of CKI in the cell cycle?
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What is the consequence of atm mutations in ataxia telangiectasia disease?
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What is the role of Ubiquitin-ligase in the cell cycle?
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What is the consequence of DNA damage on the cell cycle?
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Study Notes
Cell Cycle Control System
- The cell cycle control system is based on two key families of proteins: Cyclin-dependent protein kinases (Cdk) and Cyclins.
- Cdk phosphorylates selected proteins, inducing downstream processes.
- Cyclins bind to Cdk, forming a complex that controls their ability to phosphorylate target proteins and are cyclically synthesized and degraded.
Events Driving the Cell Cycle
- Cyclic synthesis of cyclins leads to the assembly of Cyclin-Cdk complex, which activates phosphorylation of selected proteins.
- Activation is followed by disassembly (breakdown of cyclin) and inactivation of Cdk.
Cell Cycle Complexes (in Yeast)
- Two major Cdk + Cyclin complexes:
- Cdk + mitotic cyclin = Mitosis Promoting Factor (MPF), required for entry into mitosis.
- Cdk + G1 cyclin = Start kinase, required for passage through G1 checkpoint and entry into S phase.
In Higher Eukaryotes
- The cell cycle is controlled by multiple cyclins (A, B, C, D, E) and multiple Cdk's (Cdk1-Cdk8).
- Complexes of Cyclins and Cyclin-dependent Kinases:
- Cdk4,6/ cyclin D; passage through G1 checkpoint.
- Cdk2/ cyclin E; required for G1-S transition and initiation of DNA synthesis.
- Cdk2/ cyclin A; required for progression through S phase.
- Cdk1/ cyclin B (MPF); drives G2 to M phase transition.
Mechanism of Cdk Regulation
- Association with cyclins (Formation of Cdk/cyclin complexes).
- Cyclin synthesis and degradation.
- Activating phosphorylation by CAK (Cdk activating enzyme).
- Inhibitory phosphorylation by Wee 1 (protein kinase).
- Activating dephosphorylation by Cdc25 protein phosphatase.
- Association with Cdk inhibitors CKIs.
Cdk Inhibitors (CKIs)
- Two families of Cdk inhibitors:
- Cip/Kip family (p21, p27, p57) inhibits Cdk4, 6/Cyclin D, Cdk2/Cyclin E, and Cdk2/Cyclin A.
- Ink4 family (p15, p16, p18, p19) inhibits Cdk4, 6/Cyclin D.
Mitosis Promoting Factor (MPF)
- MPF is a cytoplasmic regulator that controls the entry into mitosis.
- MPF was first discovered in mature Xenopus oocytes.
- MPF phosphorylates a set of target proteins, including lamins, condensins, and H1 histone, microtubule associated proteins (MAPs).
Discovery of MPF
- Experiments by Y. Masui and C. Markert in 1971 showed that cytoplasm from M phase oocytes was sufficient to induce entry into mitosis in G2 oocytes.
Cell Fusion Experiments
- M + G1 fusion: G1 nucleus enters into mitosis, showing that cytoplasm of M phase cells contains a potent factor (MPF) sufficient to induce entry into mitosis.
Passage through G1 Checkpoint
- Rb protein is the target protein of Cdk4,6/cyclin D complex.
- Rb is phosphorylated by Cdk4,6/cyclin D complex, leading to its inactivation.
Retinoblastoma Rb Protein
- Rb is a tumor suppressor gene.
- Inactivation of Rb leads to tumor development.
- Rb is a key substrate protein of Cdk4,6/Cyclin D (G1-Cdk).
- Activity of Rb is regulated by phosphorylation.
Start Kinase
- In G1, synthesis of G1 cyclins (cyclin D) leads to the binding of Cdk, forming a complex that phosphorylates Rb, leading to its inactivation.
- E2F activates transcription of target genes G1/S-cyclin (cyclin E), S-cyclin (cyclin A), and active S-Cdk, leading to cell entry into S phase.
DNA Damage Control Points
- p53 mutations (loss of function) prevent G1 arrest in response to DNA damage, allowing damaged DNA to be replicated and passed on to daughter cells, leading to cancer development.
Proteolysis and Inactivation of MPF
- Ubiquitin-mediated proteolysis of M-cyclin by activation of Ubiquitin-ligase called Anaphase-promoting complex (APC).
- Activation of APC leads to proteolysis of securin, activation of separase, and proteolysis of cohesins, resulting in sister chromatid separation.
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Description
This quiz covers the cell cycle control system, including the role of Cyclin-dependent protein kinases and Cyclins in regulating the cell cycle.
