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Cell cycle
This document summarizes key aspects of the cell cycle and its regulation. It describes the main phases of the eukaryotic cell cycle including interphase and mitosis. Checkpoints that ensure DNA replication fidelity like ATM/ATR pathways are discussed. Central regulators of the cell cycle like cyclins, CDKs, and CDK inhibitors are covered. The roles of Rb and p53 tumor suppressors are mentioned. The stages of mitosis and spindle assembly checkpoint are briefly outlined.
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Cell cycle
- 1. CLINICAL BIOCHEMISTRY MOHAMMAD AMIN ROLLNO:- 17 → Cell cycle. →check points. →Regulation of cell cycle ameendelina@gmail.com
- 2. Eukaryotic cell cycle:-occurs in 24 hrs. cell cycle is divided into two basic parts : mitosis(ending with cytokinesis lasts only 1 hr.) and interphase(95% time ). Phases:- 11 hrs 8 hrs 4 hrs
- 3. Regulation of cellcycle :- 1 :- extracellular signals (growth factors) which causes cell proliferation by activating cell signaling. 1st regulatory mechanism was studied in sacromyces cerevisiae a decision point known as START (nutrient and cell size depend). Saccharomyces cerevisiae regulation of cell cycle
- 4. In animalscell decision point is called a restriction point depends primarily on appropriate growth factors otherwise enter to G0 phase (e.g., skin fibroblast and liver cell) . 2:- Cell cycle checkpoints:- Several checkpoints function to ensure that incomplete or damaged chromosomes are not replicated and passed on to daughter cells. a)DNA damage response signaling pathway:- double and single stranded breaks in DNA are recognized by two proteins ATM (Ataxia Telangiectasia Mutated) and ATR (Ataxia Telangiectasia Rad 3 related) serine threonine kinases. In mammals, (Mre11/Rad50/Nbs1) double stranded breaks sensors in ATM Pathways and RPA (replication protein A ) acts as sensor in ATR pathway.
- 5. DNA DAMAGE CHECKPOINTPATHWAYS ATM PATHWAY sensor protein sensor protein
- 6. (b) Control ofDNA duplication in S-phase:- preparation begins in G1 phase with assembly of prereplicative complex that unwind DNA. Replication occurs. Activation of S-CDK in late G1 triggers formation of preinitiation complex. Thus DNA synthesis occurs. (c)Blockage of re-replication :- The S-CDK triggers the disassembly of some prereplicative complex components at the origin. Blockage is triggered by destruction of Cdc6 and the inactivation of the ORC. It ensures replication occurs only once.
- 8. ROLE OF RbIN CELL CYCLE REGULATION TSG was first discovered loss of its function causes retinoblastoma. In mammals & in fact all metazoans are regulated by Rb. Regulates G1-S phase transition.
- 9. ROLE OF p53IN CELL CYCLE REGULATION 393 amino acids, guardian of genome ,unstable in normal cell remains bound with Mdm2 (murine double min. 2) Mdm2 is E3 ubiquitin ligase. Activated by DNA damage and other stresses.
- 11. Regulation of CDKactivity Engines of cell cycle progression are protein complexes composed of two subunits Cyclin and Cyclin Dependent Kinases. These are serine/ threonine kinases. Four classes G1 cyclins, G1/S-cyclins, S-cyclins and M- cyclins. Cyclins CDKs G1 cyclin: cyclin D (cyclin D1,D2,& D3) CDK4,CDK6 G1/S-cyclin: cyclin E CDK2 S-Cyclin : Cyclin A CDK2 M-Cyclin : Cyclin B CDK1
- 15. Regulation of activityof cyclin- CDK complex Ubiquitin dependent proteolysis. Enzyme SCF (E3 ubiquitin ligase) for G1 Phase Cyclins SCF(Skp1/Cul1/F-box protein) ( its three subunits.) Second ubiquitin ligase (APC/C) anaphase promoting complex / cyclosome for S and M-Phase Cyclin destruction. Inhibitory protein kinase Wee1 phosphorylates an inhibitory tyrosine residue at 15th position in CDK subunit. Wee1 inhibits the entry into the M-phase when cell size is not adequate. Cdc25 removes it. CDK inhibitors also regulate there function . All euk… harbor CDK,s regulate S-phase and M-CDKs E.g.. INK4s for CDK4&6 they bind them and block there binding with cyclins.
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- 18. ENTRY INTO MITOSIS Processthat partitions chromosomes equally into two daughter cells. ACTIVATION OF MITOTIC CDKs Wee1 and Cdc25 regulates the M-CDK activation. Cyclin A and Cyclin B assemble to form the complex. Once M-CDKs are activated promote chromosome condensation , nuclear envelope breakdown, mitotic spindle formation, chromosomal alignment.
- 19. STAGES OF MITOSIS Karyokinesisor mitosis and cytokinesis PROPHASE Condensation of chromatin into well defined chromosomes. Disruption of nuclear membrane. Lower eukaryotes undergo (closed mitosis) and higher eukaryotes undergo ( open mitosis ) METAPHASE Mitotic spindles grow out of MTOC. Attachment with kinetochores (by search and capture). Microtubule dependent motor proteins drive the movement of chromosome towards poles. Alignment of chromosomes on the metaphase plate called congression .
- 21. Spindle Assembly Checkpoint(SAC):- Involves sensing mechanism bases on tension on kinetochores Aurora B associated proteins or chromosomal passenger complex (CPC) . Aurora B phosphorylates the microtubule binding subunits of the kinetochores, destabilizing any microtubule attachment. Tension lacking kinetochores Chk1 Aurora B Bub1 + BubR1 + Mad2APC/C Cdc20 Metaphase Anaphase MITOTIC CHECKPOINT
- 22. ANAPHASE Degradation of cohesionsby separase. Separation of chromatids.
- 25. TELOPHASE Separated chromosomes arriveat the poles and microtubules disappear. Nuclear envelope re-forms, chromosomes expand, mitosis end. CYTOKINESIS Douglas Marsland in 1950’s proposed this theory. Contractile Ring Theory. Contractile proteins assembled at center by G protein Rho in GTP bound state.