The cell cycle is controlled by mechanisms both internal and external to the cell, and by regulator molecules.

The cell cycle is controlled at three internal checkpoints. Damage to DNA and other external factors are evaluated at the G1 checkpoint; if conditions are inadequate, the cell will not be allowed to continue to the S phase of interphase.

The G2 checkpoint ensures all of the chromosomes are replicated and that the replicated DNA is not damaged before the cell enters mitosis. The M checkpoint determines whether all the sister chromatids are attached to the spindle microtubules. This is important before the cell enters anaphase.

The cell cycle is also controlled by regulator molecules that either promote the process or stop it from progressing. Two groups of proteins, cyclins and cyclin-dependent kinases (Cdks), are responsible for promoting the cell cycle. Cyclins regulate the cell cycle only when they are bound to Cdks. To be activated, the Cdk/cyclin complex must be phosphorylated, which allows it to phosphorylate other proteins that advance the cell cycle.

Negative regulator molecules (Rb, p53, and p21) act primarily at the G₁ checkpoint and prevent the cell from moving forward to division until damaged DNA is repaired. p53 halts the cell cycle and recruits enzymes to repair damaged DNA; if DNA cannot be repaired, p53 triggers apoptosis to prevent duplication. Production of p21 is triggered by p53; p21 prevents the cycle by binding to and inhibiting the activity of the Cdk/cyclin complex. Dephosphorylated Rb binds to E2F, which halts the cell cycle; when the cell grows, Rb is phosphorylated and releases E2F, which advances the cell cycle.

Key Points

• A checkpoint is one of several points in the eukaryotic cell cycle at which the progression of a cell to the next stage in the cycle can be stopped until conditions are favorable.

• The G₁ checkpoint monitors adequate cell growth, the state of the genomic DNA, adequate stores of energy, and materials for S phase.

• At the G₂ checkpoint, DNA is checked to ensure that all chromosomes were duplicated and that there are no mistakes in newly synthesized DNA. Additionally, cell size and energy reserves are evaluated.

• The M checkpoint confirms the correct attachment of the mitotic spindle fibers to the kinetochores.

• Positive cell regulators such as cyclin and Cdk perform tasks that advance the cell cycle to the next stage.

• Negative regulators such as Rb, p53, and p21 block the progression of the cell cycle until certain events have occurred.

• Cdk must bind to a cyclin, and it must be phosphorylated in the correct position to become fully active.

• Rb and other negative regulatory proteins control cell division, so they prevent the formation of tumors.

Key Terms

G1 checkpoint: a point in the animal cell cycle at which the cell becomes “committed” to the cell cycle, which is determined by external factors and signals

sister chromatid: either of the two identical strands of a chromosome (DNA material) that separate during mitosis

M checkpoint: prevents separation of the duplicated chromosomes until each chromosome is properly attached to the spindle apparatus

cyclin: any of a group of proteins that regulates the cell cycle by forming a complex with kinases

cyclin-dependent kinase (Cdk): (CDK) a member of a family of protein kinases first discovered for its role in regulating the cell cycle through phosphorylation

E2F: which is a transcription factor required for the transcription and eventual translation of molecules required for the G₁/S transition.

p21:  cell cycle regulatory protein that inhibits the cell cycle; its levels are controlled by p53

p53:  cell cycle regulatory protein that regulates cell growth and monitors DNA damage; it halts the progression of the cell cycle in cases of DNA damage and may induce apoptosis

retinoblastoma protein (Rb): a group of tumor-suppressor proteins that regulates the cell cycle by monitoring cell size

phosphorylate: the addition of a phosphate group as a modification