Checkpoints, cyclins and CDKs

Who decides when a cell divides?

A cell in your skin may divide every few days. A nerve cell never divides. A cell with damaged DNA must not divide at all. Something decides. That something is the control system of the cell cycle. It works like a train signal. The cycle goes on only when the signal is green.

NCERT says that the events of the cell cycle are under genetic control, but it does not name the checkpoints or the proteins. A-Level, IB and AP do. NEET asks about them less often than about mitosis. They are the key to understanding cancer, which is the next lesson.

The three checkpoints

A checkpoint is a point at which the cell is checked, and the cycle can be stopped.

• G1 checkpoint (also called the G1/S checkpoint or the restriction point). At the end of G1, the cell checks its size, its food, the growth factors from outside and the DNA for damage. If all is well, the cell commits to a division. If not, it pauses to repair, or it goes into G0.
• G2 checkpoint (the G2/M checkpoint). At the end of G2, the cell checks that all the DNA is copied and undamaged. If not, it finishes the copying or repairs the DNA before mitosis.
• Spindle checkpoint (the M checkpoint). In metaphase, before anaphase, the cell checks that every pair of sister chromatids is attached to spindle fibres from both poles. Anaphase cannot be undone, so the cell waits until all are attached.

Cyclins and CDKs: the engine

What switches a checkpoint on? A pair of proteins.

• A CDK is a cyclin-dependent kinase. A kinase is an enzyme that adds phosphate groups to other proteins. This changes what those proteins do. A CDK is present in a steady amount all through the cycle, but it is inactive alone.
• A cyclin is a protein whose amount rises and falls through the cycle. When a cyclin binds a CDK, the CDK becomes active (after a second kinase adds a phosphate to it).
• There are four kinds of cyclin that work at different times: G1 cyclins, G1/S cyclins, S cyclins and M cyclins. After its job is done, a cyclin is broken down.

The M cyclin with its CDK is the complex that pushes the cell into mitosis. It is also called MPF, the M phase promoting factor. It makes the chromosomes condense, the nuclear envelope break down and the spindle form. At the end of metaphase the M cyclin is broken down. The CDK is switched off, and the cell leaves mitosis.

The brakes: p53, p21 and Rb

The system also has proteins that stop the cycle.

• p53 responds to damaged DNA. It halts the cycle and calls in repair enzymes. If the damage cannot be repaired, p53 can start apoptosis, the planned death of the cell. A rise in p53 raises the amount of p21.
• p21 binds the CDK and cyclin complexes and blocks them. This enforces the halt that p53 asks for.
• Rb (the retinoblastoma protein) binds a protein called E2F while it is unphosphorylated. E2F is needed to switch on the genes of S phase. When a growth signal arrives, a G1 CDK adds phosphate to Rb. Rb lets go of E2F, and the cell goes into S phase.

The names p53 and p21 come from the masses of the proteins, in kilodaltons.

Cells that stop at G0

If conditions are poor, a cell may leave the cycle at the G1 checkpoint and enter G0, as NCERT describes. Some cells, such as most nerve cells, stay in G0 for life. Others return to the cycle when a signal tells them to.

You should see that the cell stops at the first checkpoint that it fails, and that the checkpoints after it are not reached. Damage to the DNA can stop the cell at either the G1 or the G2 checkpoint.

Try it in Python

The program checks four cells against the three checkpoints.

Practise with new numbers

Common mistakes

• Saying that a CDK is made only when it is needed. The amount of CDK is steady. The cyclin amount changes.
• Saying that a cyclin is an enzyme. The CDK is the enzyme (a kinase). The cyclin switches it on.
• Placing the spindle checkpoint before metaphase. It acts at metaphase, before anaphase.
• Thinking that p53 speeds up the cycle. It is a brake. It halts the cycle.
• Mixing up Rb and p53. Rb holds back E2F. p53 senses damage and raises p21.

Remember these

• Three checkpoints: G1 (size, food, growth factors, DNA damage), G2 (DNA copied and undamaged), spindle (all chromosomes attached).
• CDK: steady amount, inactive alone. Cyclin: rises and falls, switches the CDK on.
• M cyclin and CDK (MPF) start mitosis. Breaking down the M cyclin ends it.
• p53, p21 and Rb are brakes. They are tumour suppressors.

Check yourself

Try each one on your own first. If you are stuck, open a hint. Then check with Show the answer.

1. Name the three checkpoints and say what each one checks.

2. Why is a CDK called cyclin-dependent?

3. How does the amount of a cyclin change through the cycle, and how does the amount of its CDK change?

4. What does p53 do when the DNA is damaged?

5. Why does the cell wait at the spindle checkpoint?

References

• Clark M. A., Douglas M. and Choi J. (2018). Biology 2e, OpenStax, chapter 10.3, Control of the Cell Cycle.
• NCERT (2023). Biology, Textbook for Class XI, chapter 10, for the G0 stage and the genetic control of the cycle.