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The cell cycle is the ordered sequence of events by which a cell duplicates its contents and divides into two daughter cells. It consists of interphase (G1, S, G2) and mitosis (M). Progression is tightly regulated by cyclins, cyclin-dependent kinases (CDKs), and three major checkpoints that safeguard genomic integrity. Cell cycle dysregulation underlies most cancers.
- G1 (gap 1): Cell grows and produces proteins needed for DNA replication. Length is variable; cells may exit to a resting state called G0.
- S (synthesis): DNA is replicated, producing sister chromatids held together at the centromere. Each chromosome now has 2 chromatids (4N DNA content at end of S).
- G2 (gap 2): Cell continues to grow and produces proteins needed for mitosis. DNA is double-checked for errors.
- M (mitosis): Nuclear division (prophase → metaphase → anaphase → telophase) followed by cytokinesis. Produces two genetically identical diploid daughter cells.
- G1/S checkpoint (restriction point): Cell commits to DNA replication. Regulated by p53 and Rb. DNA damage here halts the cycle; if unrepairable, p53 triggers apoptosis.
- G2/M checkpoint: Verifies DNA replication is complete and undamaged before mitosis.
- Spindle assembly checkpoint (SAC, metaphase): Ensures all chromosomes are correctly attached to the mitotic spindle before anaphase. Failure causes aneuploidy (nondisjunction).
- Cyclins (D, E, A, B) rise and fall during the cycle; each activates a specific CDK (cyclin-dependent kinase).
- CDK4/6-Cyclin D drives G1 progression; CDK4/6 inhibitors (palbociclib) are used clinically in breast cancer.
- p53 ("guardian of the genome") is mutated in more than half of cancers; germline loss causes Li-Fraumeni syndrome.
- Rb (retinoblastoma protein) restrains G1→S entry; germline loss causes retinoblastoma and predisposes to osteosarcoma.
- Cancer: checkpoint loss (p53, Rb, BRCA1/2) allows damaged cells to replicate. Hallmarks of cancer include sustained proliferative signaling and evasion of growth suppressors.
- Aneuploidy: SAC defects lead to errors during mitosis in somatic cells (mosaic aneuploidy) or meiosis (congenital aneuploidy like trisomy 21).
- Chemotherapy: many cytotoxic agents target specific phases (e.g., methotrexate blocks S phase; vincristine and taxanes target the M-phase spindle).
- Sister chromatids are produced in S phase and separate in anaphase of mitosis (or anaphase II of meiosis).
- p53 senses damage; Rb controls G1→S commitment. Don't confuse their roles.
- Somatic cells undergo mitosis only; germ cells undergo both mitosis (to produce spermatogonia/oogonia) and meiosis (to produce gametes).