Cell Cycle, Mitosis & Meiosis

Cell division is the basis of growth, tissue repair, and reproduction. The cell cycle is a tightly regulated sequence of events that ensures accurate genome duplication and equal distribution to daughter cells. Defects in cell cycle control underlie cancer.

The Cell Cycle

The cell cycle consists of interphase and mitosis (M phase). Interphase is divided into G1 (first gap/growth phase), S (DNA synthesis), and G2 (second gap/preparation for mitosis). Cells that have exited the cycle enter a quiescent state called G0 (e.g., terminally differentiated neurons, most hepatocytes).

G1 phase is the primary growth phase during which cells increase in size, synthesise proteins, and respond to mitogenic signals. The restriction point (R point) late in G1 is a critical commitment point: once passed, the cell is committed to completing the cycle regardless of extracellular signals.

S phase lasts ~8 hours in human cells. DNA replication initiates at ~30,000 origins simultaneously, each firing once and only once per cycle (ensured by licensing: MCM loading in G1, removal of licensing factors after firing).

G2 phase is a second growth and quality-control period. Cells check that DNA replication is complete before entering mitosis.

Cyclins and CDKs

Cell cycle progression is driven by cyclin-dependent kinases (CDKs) — constitutively expressed serine/threonine kinases that are inactive without a cyclin partner. Cyclins fluctuate in abundance through the cycle, activating CDKs at specific transitions.

• Cyclin D/CDK4,6: synthesised in response to mitogens (EGF, FGF) in G1; phosphorylate the retinoblastoma protein (Rb), releasing the transcription factor E2F to activate S-phase genes (including cyclin E, DHFR, thymidylate synthase). CDK4/6 inhibitors (palbociclib, ribociclib) are used in HR+ breast cancer.
• Cyclin E/CDK2: drives the G1→S transition; phosphorylates Rb to complete inactivation.
• Cyclin A/CDK2: required for S phase; phosphorylates replication factors.
• Cyclin B/CDK1 (MPF — maturation-promoting factor): drives mitotic entry; phosphorylates lamins (nuclear envelope breakdown), condensins (chromosome condensation), and many other substrates.

CDK inhibitors include the INK4 family (p16^INK4a/CDKN2A, p15, p18, p19 — inhibit CDK4/6) and the CIP/KIP family (p21^CIP1/CDKN1A, p27, p57 — inhibit multiple CDK complexes). p21 is directly induced by p53 in response to DNA damage, coupling the DNA damage response to G1 arrest.

Cell Cycle Checkpoints

Three major checkpoints prevent propagation of errors. The G1/S checkpoint assesses DNA integrity and adequacy of growth signals before committing to replication. Activation of ATM/ATR kinases by DNA damage leads to Chk1/Chk2 activation, which phosphorylate and degrade Cdc25A phosphatase → CDK2 remains inactive → G1 arrest. Simultaneously, p53 is stabilised (MDM2 phosphorylation prevents ubiquitination) and activates p21 transcription. The G2/M checkpoint verifies complete and accurate replication. ATM/ATR→Chk1/Chk2→Cdc25C phosphorylation sequesters Cdc25C in the cytoplasm → CDK1 remains phosphorylated and inactive → G2 arrest. The spindle assembly checkpoint (SAC) at metaphase ensures all kinetochores are properly attached to spindle microtubules. Unattached kinetochores generate the mitotic checkpoint complex (MCC: Mad2, BubR1, Bub3), which inhibits the anaphase-promoting complex/cyclosome (APC/C). APC/C^Cdh1 is only activated when all chromosomes are correctly bioriented → securin degradation releases separase → cohesin cleavage → sister chromatid separation.

Mitosis

Mitosis (PMAT): Prophase — chromosomes condense (condensins); centrosomes (each with two centrioles) migrate to opposite poles; mitotic spindle nucleates from γ-tubulin rings at centrosomes. Prometaphase — nuclear envelope breaks down (lamin phosphorylation by CDK1); spindle microtubules capture kinetochores; chromosomes congress toward the cell equator. Metaphase — chromosomes align at the metaphase plate; SAC satisfied when all kinetochores are under tension from bioriented kinetochore microtubules. Anaphase A — cohesin cleavage allows sister chromatid separation; kinetochore microtubule shortening pulls chromosomes poleward. Anaphase B — elongation of interpolar microtubules pushes poles apart. Telophase/Cytokinesis — nuclear envelopes reform; chromosomes decondense; actomyosin contractile ring (positioned by the central spindle) constricts, cleaving the cell.

Meiosis

Meiosis produces haploid gametes from diploid precursors through two sequential divisions (meiosis I and II) with a single round of DNA replication. Meiosis I (reductional division) separates homologous chromosome pairs. Unique features of prophase I: chromosomes pair (synapsis) via the synaptonemal complex; crossing over (recombination) at chiasmata between non-sister chromatids of homologues generates genetic diversity and physically holds homologues together until metaphase I. This is the longest phase (~days in oogenesis, arrested at prophase I from fetal life to ovulation). Meiosis II separates sister chromatids (analogous to mitosis). Errors in meiotic segregation (non-disjunction) cause aneuploidy: trisomy 21 (Down syndrome), trisomy 18 (Edwards), trisomy 13 (Patau), monosomy X (Turner), XXY (Klinefelter). Non-disjunction risk increases with maternal age due to premature dissolution of chiasmata (the two-hit model of cohesion fatigue).