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DNA damage checkpoint - prevents progression through the cell cycle until the damage is repaired. Arrests at G1,S and G2 ATM and p53.

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  1. DNA damage checkpoint - preventsprogression through the cell cycle until the damage is repaired. Arrests at G1,S and G2 ATM and p53 G2 checkpoint – triggers entry into mitosis by maturation promoting factor (MPF) (formed from Cyclin B and CDC2) and activated by CDC 25. MPF= M Cyclin and M CDK Spindle-assembly checkpoint - confirms that all the chromosomes are properly attached to the spindles. Chromosome-segregation checkpoint - confirms that the chromosomes have segregated to the poles triggering division. ATM – checks DNA for damage. If it finds damage it activates Chk2 which phosphorylates CDC25 preventing it from activating MPF. It also stabilises p53the guardian of the genome which can synthesis CKI’s, DNA repair enzymes and cause apoptosis Resting phase (G0) – non-proliferative phase - can remain in for long periods of time. Common for fully differentiated cell. Mitotic CDKs (MPF) (M) 1 hr 4-6 hr • 4. Mitotic cyclins trigger: • Chromosome condensation • Assembly of the mitotic spindle • Breakdown of nuclear envelope 10-12 hr G1 checkpoint – is environment right for division? G1-phase CDK’s 8 hr S-phase CDKs

  2. G1-phase CDKs P Rb Rb G1 cyclin E2F E2F G1 CDK Growth factors induce synthesis of G1 cyclins – GF RAS-GTPRAF MEK-PMAPK-PTF G1 cyclin Retinoblastoma protein prevents release of E2F 1. G1 cyclins activate G1 CDKs 2. Phosphorylation of Rb releases E2F 4. Synthesis of proteins required for entry into S phase 3. E2F transcription factor regulates expression of specific genes DNA

  3. S-phase CDKs G1 cyclin CKI CKI S cyclin S cyclin G1 CDK S CDK S CDK P CKI CKI CKI Growth inhibitory factors induce synthesis of CKIs – SMADSMAD-P SMAD-coSMADTF CKI 2. S-phase CDKs are activated by the release of CKIs Replication complex P 3. Phosphorylation of replication complex triggers DNA synthesis 1. Phosphorylation of CKI triggers its degradation

  4. Replication complex Mitotic CDKs M cyclin M CDK 1. Completion of DNA synthesis releases replication complex Replication complex Phosphorylation of: Histones Microtubules Lamins Inhibitory phosphate M cyclin P M CDK 2. Replication complex causes activation of a phosphatase (CDC 25) Mitotic cyclins trigger: Chromosome condensation Assembly of the mitotic spindle Breakdown of nuclear envelope

  5. Replication complex Mitotic CDKs M cyclin M CDK 1. Completion of DNA synthesis releases replication complex Replication complex 2. Replication complex causes activation of a phosphatase (CDC25) Phosphorylation of: Histones Microtubules Lamins M cyclin P M CDK Inhibitory phosphate 3. CDC25 phosphatase activates MPF (M CDK complex) • 4. Mitotic cyclins trigger: • Chromosome condensation • Assembly of the mitotic spindle • Breakdown of nuclear envelope

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