1. 1 hr 10-12 hr 8 hr 4-6 hr (M) Spindle-assembly checkpoint - confirms that all the chromosomes are properly attached to the spindles. Resting phase (G0) – non- proliferative phase - can remain in for long periods of time. Common for fully differentiated cell. Chromosome- segregation checkpoint - confirms that the chromosomes have segregated to the poles triggering division. DNA damage checkpoint - prevents progression 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 G1 checkpoint – is environment right for division? G1-phase CDK’s S-phase CDKs Mitotic CDKs (MPF) 4. Mitotic cyclins trigger: Chromosome condensation Assembly of the mitotic spindle Breakdown of nuclear envelope ATM – checks DNA for damage. If it finds damage it activates Chk2 which phosphorylates CDC25 preventing it from activating MPF. It also stabilises p53 the guardian of the genome which can synthesis CKI’s, DNA repair enzymes and cause apoptosis

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

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

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

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