AH Biology: Unit 1 Control of the Cell Cycle

The cell cycle: summary G1G1 G2G2 S Interphase M Cytokinesis Mitosis

The cell cycle: summary G1G1 G2G2 S Interphase M Cytokinesis Telophase Anaphase Prophase Metaphase Mitosis

­ Why does the progress of a cell through the cell cycle need to be monitored and regulated? ­ What features should an effective cell cycle control system possess?

The cell cycle control system can be studied using model organisms Yeast: Identification of mutations that arrest the cell cycle at specific points. Affected genes are known as cell-division-cycle (cdc) genes.

The cell cycle contains control points G1G1 G2G2 S I M G 1 checkpoint (entry to S phase) G 2 checkpoint (entry to M phase) M checkpoint (exit from M phase)

The cell cycle contains control points G1G1 G2G2 S I M G 1 checkpoint (initiation of DNA replication) G 2 checkpoint (assembly of spindle fibres) M checkpoint (initiation of anaphase)

The control points are checkpoints for the cell cycle control system If events have not been completed the control system receives signals and arrests the cell cycle. G1G1 G2G2 S I M G 1 checkpoint: Has the cell reached a sufficient size? Are environmental conditions favourable? G 2 checkpoint: Has all nuclear DNA been replicated? M checkpoint: Are all chromsomes attached to spindle fibres?

The G 1 checkpoint Timing: Towards the end of G 1 phase. Controls: Entry to S phase (triggers the initiation of DNA replication). Assesses: Cell size and environmental conditions. Purpose: Ensures that sufficient cell growth has occurred and environmental conditions are favourable for proliferation.

What could happen to a yeast cell whose G 1 checkpoint mechanism has been inactivated?

Cell size Time With nutritional cell cycle control Nutrient supply reduced Without nutritional cell cycle control

In multicellular organisms the G 1 checkpoint operates through intracellular and extracellular signals Fibroblast grown in culture with adequate nutrient supply and serum Fibroblast grown in culture with adequate nutrient supply and plasma Cell progresses through cycle and proliferates Cell cycle is arrested

Serum contains a protein that can bind to cells and stimulate them to progress through the cell cycle. Extracellular signal molecules with this function are called mitogens.

The most important decision Cells may either proliferate or leave the cell cycle. In the absence of mitogens cells enter a non- dividing state called the G 0 phase. Cells can become terminally differentiated and remain in G 0 permanently or re-enter the cell cycle when they receive appropriate signals.

G1G1 G2G2 S Interphase M Cytokinesis Mitosis G0G0 Reversibility depends on cell type

Some types of cell can proliferate continuously Stem cells Tumour cells

Most liver cells exist in a reversible G 0 phase G1G1 G2G2 S I M G0G0 G1G1 G2G2 S I M G0G0 Normal hepatocyte: mitogenic signal absent Cell proliferation is stimulated by damage to liver

Red blood cells, neurons and skeletal muscle cells exist in a terminally differentiated G 0 state

The G 2 checkpoint Timing: End of G 2 phase. Controls: Entry to M phase (triggers assembly of mitotic structures). Assesses: Completion of DNA replication. Purpose: Ensures that all DNA is replicated so that daughter cells can each receive a complete copy of the genome and function correctly.

The M checkpoint Timing: During metaphase. Controls: Exit from M phase (triggers anaphase and cytokinesis). Assesses: Attachment of all chromosomes to spindle fibres. Purpose: Ensures that each daughter cell receives the same chromosome complement as its parent when anaphase occurs.

The M checkpoint All chromosomes attached to spindle fibres One chromosome is not attached to spindle fibres Cell cycle progresses: cell enters anaphase Cell cycle arrested until all chromosomes are properly attached

Checkpoints operate through negative intracellular signals The presence of unattached chromosomes generates signals that stop the cell from progressing to anaphase.

The molecular mechanisms of cell cycle control

The cell cycle is controlled by the activity of cyclin-dependent kinases (Cdks) G1G1 G2G2 S M Cdk active Cdk inactive

The cell cycle control system can be studied using model organisms Spisula: a mollusc used in the study of protein synthesis (eg of cyclins) in embryonic cells.

A time course of intracellular cyclin protein Time Relative level of cyclin protein Mitosis

The activity of Cdks is regulated by cyclins Inactive Cdk Cyclin binding Cdk with protein kinase activity (cyclin–cdk complex)

Different cyclins bind to Cdks at different phases of the cell cycle -The binding of G 1 -cyclins allows a cell to pass through the G 1 checkpoint. -The binding of S-cyclins allows a cell to initiate DNA replication in the S phase. -The binding of M-cyclins promotes the events of mitosis.

The activation of cyclin-Cdk complexes triggers cell cycle events A certain level of phosphorylation of target proteins results in the cell progressing to the next stage of the cycle. G1G1 G2G2 S M Mitosis triggered DNA replication triggered M-Cdk S-Cdk G 1 -Cdk

Active retinoblastoma protein (Rb) inhibits cell cycle progression SG1G1

Retinoblastoma is targeted by G 1 -Cdk Active G 1 -Cdk PP Active RbInactive Rb What would be the consequence of a mutation to the gene that codes for the Rb protein? Synthesis of S-cyclins Active S-Cdk DNA replication

The cell cycle has checkpoints for DNA damage Mutagen In which part(s) of the cell cycle would you expect these checkpoints to occur? What should a cell with damaged DNA do?

DNA damage prior results in the activation of the protein p53 1. Damaged DNA 2. Protein kinase activity triggered Unstable p53 Stable p53 P

Active p53 can promote the transcription of genes that induce cell cycle arrest P Regulatory DNA Expression of p21 gene p21 protein Cyclin–Cdk complex inactivated Cell arrested in G 1

Active p53 can affect a cell in different ways What would be the functional consequences of an inability to activate p53? P Stimulates DNA repair Promotes transcription of genes that induce apoptosis Promotes transcription of genes that induce cell cycle arrest

Ataxia telangiectasia: a genetic disease associated with an inability to activate p53 What could cause the development of telangiectases (small clusters of enlarged blood vessels)?

Cell cycle review Interactive cell cycle animation.animation Control of cell cycle game on the Nobel Prize website (simulation). website AnimationAnimation of the action of the Rb and p53 proteins.