Cell Cycle Regulation, Mitosis & Meiosis

Phases of the cell cycle

The sequence. Dividing cells pass through G1 (growth), S (DNA synthesis: content doubles from 2c to 4c while the chromosome count stays 46), G2 (further growth and checking of replicated DNA) and M (mitosis, then cytokinesis). S, G2 and M take fairly constant times, whereas G1 stretches or shrinks with growth signals and so sets cycle length. At the restriction point in late G1 the cell commits and finishes the cycle even if growth factors are withdrawn. G0 is a quiescent state outside the cycle.

• Labile cells cycle continuously: bone marrow, gut and skin epithelium, hair follicles.
• Stable cells rest in G0 but re-enter G1 when stimulated: hepatocytes (liver regrowth after partial hepatectomy), lymphocytes, proximal tubule cells.
• Permanent cells have left the cycle: neurons, cardiac and skeletal muscle, RBCs; injury heals by scarring.

Cyclins, CDKs and the Rb gate

Engines. Cyclin-dependent kinases are present throughout the cycle but active only when bound to a cyclin. Each cyclin is made at a set time and then destroyed by ubiquitin-mediated proteolysis, which keeps the cycle moving in one direction.

Brakes. p16 (INK4 family, gene CDKN2A) blocks CDK4/6 specifically; germline CDKN2A mutations cause familial melanoma with raised pancreatic cancer risk. p21 and p27 (Cip/Kip family) inhibit a broad range of complexes: p53 induces p21 after DNA damage, and p27 mediates contact inhibition and TGF-β-induced arrest.

The Rb–E2F switch. Hypophosphorylated Rb binds E2F and represses S-phase genes (cyclin E, DNA polymerase, dihydrofolate reductase, thymidine kinase). Cyclin D-CDK4/6 begins and cyclin E-CDK2 completes Rb phosphorylation; E2F is released, cyclin E rises in a positive feedback loop, and the cell passes the restriction point.

CDK4/6 inhibitors. Palbociclib, ribociclib and abemaciclib keep Rb hypophosphorylated and arrest cells in G1. With an aromatase inhibitor or fulvestrant they treat HR-positive, HER2-negative advanced breast cancer, and they need functional Rb. Toxicities: neutropenia (palbociclib, ribociclib), diarrhea (abemaciclib), QT prolongation (ribociclib).

Viruses and Rb loss. High-risk HPV E7 binds Rb and frees E2F; E6 targets p53 for ubiquitin-mediated destruction and also activates telomerase. Adenovirus E1A/E1B and SV40 large T antigen hijack the same two proteins. Losing both RB1 copies causes retinoblastoma; in hereditary cases every cell already carries one mutant allele, so one somatic hit suffices, tumors are early and bilateral, and osteosarcoma risk rises later.

Checkpoints and their failures

DNA-damage checkpoint. Double-strand breaks activate ATM; single-stranded DNA at stalled forks activates ATR. Through Chk2 and Chk1 they stabilize p53 by freeing it from MDM2, the E3 ligase that normally keeps it low. p53 then induces p21 (G1 arrest for repair) and MDM2 (negative feedback), and if damage is irreparable it induces the pro-apoptotic proteins BAX, PUMA and NOXA. Chk1 and Chk2 also inactivate Cdc25, holding CDK1 off for a G2 arrest.

Inherited checkpoint failure. Li-Fraumeni syndrome (germline TP53) brings early sarcomas, breast and brain tumors, adrenocortical carcinoma and leukemia. Ataxia-telangiectasia (biallelic ATM loss) causes cerebellar ataxia, telangiectasias, IgA deficiency with sinopulmonary infections, high AFP, lymphoma risk and extreme radiosensitivity; contrast xeroderma pigmentosum, a nucleotide excision repair defect with UV sensitivity.

Spindle assembly checkpoint. Unattached kinetochores send a Mad2-dependent signal that inhibits the anaphase-promoting complex bound to Cdc20 (APC/C-Cdc20).

Mitosis and meiosis

Mitosis. In prophase condensin compacts the chromosomes and the spindle forms; in prometaphase the nuclear envelope breaks down and kinetochores capture microtubules; in metaphase chromosomes align at the plate (karyotypes are prepared from cells arrested here with colchicine); in anaphase sister chromatids move to opposite poles; in telophase nuclei re-form and an actin-myosin ring divides the cytoplasm. The result is two identical diploid cells.

Spindle poisons. Vinca alkaloids (vincristine, vinblastine) and colchicine prevent tubulin polymerization; taxanes (paclitaxel, docetaxel) block depolymerization. Both engage the spindle checkpoint and trap cells in M phase.

Gametogenesis. Primary oocytes enter meiosis in the fetal ovary and arrest in prophase I (diplotene) until ovulation, which begins at puberty. Each cycle the LH surge completes meiosis I just before ovulation, giving a secondary oocyte and the first polar body; the secondary oocyte arrests in metaphase II and finishes meiosis II, releasing the second polar body, only if fertilized. The decades-long prophase I arrest lets cohesion weaken, which is why meiosis I nondisjunction rises with maternal age. Spermatogenesis runs continuously from puberty, and each primary spermatocyte yields four sperm.

Telomeres and cell-cycle pharmacology

Telomeres. Chromosome ends carry tandem TTAGGG repeats. Because lagging-strand synthesis cannot copy the extreme end, telomeres shorten with each division; critically short telomeres are sensed as DNA damage, activate p53 and cause replicative senescence (the Hayflick limit). Telomerase, a reverse transcriptase (RNA-dependent DNA polymerase) carrying its own RNA template, extends the 3′ end in germ cells, stem cells and most cancers. Inherited telomerase defects cause dyskeratosis congenita: nail dystrophy, reticulated skin pigmentation, oral leukoplakia, marrow failure and pulmonary fibrosis.

Rb (G1/S gate) and p53 (DNA-damage response) are the central gatekeepers: HPV E7 disables Rb and E6 disables p53.

Patients with ataxia-telangiectasia should avoid unnecessary ionizing radiation, including CT scans and standard radiotherapy doses, because their cells cannot respond to double-strand breaks.