Cell Cycle

How the cell cycle works

A cell cannot divide on a whim. It must double its DNA, double its organelles, and physically partition the contents — in that order, without skipping a step. The cell cycle is the program that enforces this order. It runs on an internal clock built from cyclin-CDK complexes, with checkpoints that can stop the clock if something is wrong.

The cycle is split into interphase (G1, S, G2 — the cell prepares to divide) and mitosis (M — the cell physically divides). Most of the time is spent in interphase. M phase, despite being the visually dramatic part biology textbooks emphasize, takes only about an hour in a 24-hour cycle.

     ┌──────────────── INTERPHASE ────────────────┐    ┌── M ──┐
     │                                             │    │       │
     │   G1            S            G2             │    │  PMAT │
─→ ───┤  growth   →  DNA copy  →   growth & QC     ├──→ ┤ split ├──→ next G1
     │  ~11 hr       ~8 hr         ~4 hr           │    │ ~1 hr │
     │                                             │    │       │
     │      ↑                  ↑                   │    │   ↑   │
     │   restriction       G2/M check              │    │ spindle
     │   (G1/S)            (DNA OK?)               │    │  check│
     └─────────────────────────────────────────────┘    └───────┘

           ↓ exit to G0 (quiescent / non-dividing)

G1 (Gap 1): the cell grows and decides whether to commit to division. Mitogens (PDGF, EGF, insulin-like growth factors) drive expression of cyclin D, which activates CDK4/6. The complex phosphorylates retinoblastoma protein (Rb), releasing transcription factor E2F to turn on S-phase genes (cyclin E, DNA polymerase subunits, origin recognition complex).

S (Synthesis): the cell replicates its DNA. Each chromosome becomes two sister chromatids held together by cohesin. Cyclin E-CDK2 fires origins; cyclin A-CDK2 keeps replication forks moving. The centrosome — future spindle pole — also duplicates here.

G2 (Gap 2): growth and quality control. Cyclin B-CDK1 (originally MPF, maturation-promoting factor, in frog oocytes) accumulates in inactive form, held in check by inhibitory phosphorylations.

M (Mitosis): the dam breaks. CDC25 phosphatase strips inhibitory phosphates off cyclin B-CDK1, the kinase activates explosively, and within minutes the nuclear envelope dissolves, chromosomes condense, and the spindle assembles. M has substages — prophase, prometaphase, metaphase, anaphase, telophase — followed by cytokinesis. Cyclin B is then destroyed by ubiquitin-mediated proteolysis, CDK1 inactivates, daughters re-form nuclear envelopes, and the cycle resets to G1.

The cyclin-CDK engine

Cyclin-dependent kinases are the central drivers. CDKs are protein kinases that, on their own, are catalytically dead; they must be bound to a cyclin to phosphorylate substrates. Cyclins are named for the fact that their concentrations cycle — synthesized at one phase, destroyed at the next. Cyclin levels are the wave; CDKs are the surfboard.

Phase	Cyclin	CDK	Key substrate	Effect
Early G1	D (D1, D2, D3)	CDK4, CDK6	Rb (partial)	Begins releasing E2F
Late G1 / S	E (E1, E2)	CDK2	Rb (full), p27	Crosses restriction point
S	A	CDK2	CDC6, MCM	Fires replication origins
S / G2	A	CDK1	Origin licensing	Prevents re-replication
G2 / M	B (B1, B2)	CDK1	Lamins, condensins, APC	Drives mitotic entry
Anaphase exit	(B destroyed)	—	—	APC/C ubiquitinates cyclin B; mitosis ends

In yeast, a single CDK (Cdc28 in budding yeast, Cdc2 in fission yeast) does the work of all four mammalian CDKs by partnering with different cyclins. The discovery that human CDK1 could substitute for yeast Cdc2 in a complementation experiment — that the cell cycle engine had been conserved across a billion years of evolution — earned Hartwell, Hunt, and Nurse the 2001 Nobel Prize.

Checkpoints — surveillance, not scheduling

Checkpoints are not steps in the cycle. They are surveillance systems that halt the cycle when something goes wrong. A healthy cell sails through them; a damaged cell trips an alarm.

G1/S restriction point — the most consequential decision. The cell asks: am I big enough? Nutrients? Mitogens? DNA undamaged? (In yeast: START.) Once passed, the cell is committed even if conditions deteriorate. DNA damage activates ATM/ATR kinases, which stabilize p53. p53 transcribes p21, a CDK inhibitor that silences cyclin E-CDK2, freezing the cell until repair finishes — or, if damage is unrepairable, p53 triggers apoptosis.

G2/M checkpoint verifies S phase completed and DNA is intact. Damage keeps cyclin B-CDK1 in its Wee1-phosphorylated inactive state.

Spindle assembly checkpoint (SAC) operates inside M phase. Anaphase begins only when every kinetochore is attached to microtubules from both poles. Unattached kinetochores generate a "wait" signal (the MCC complex with Mad2 and BubR1) that inhibits the anaphase-promoting complex. Lose this and chromosomes mis-segregate — aneuploidy, a hallmark of cancer.

Cell cycle across organisms

	E. coli	S. cerevisiae	Frog embryo	Human somatic	Plant meristem	Cancer cell
Cycle time (ideal)	~20 min	~90 min	~30 min	~24 hr	~12–24 hr	~16–24 hr
Phases present	No formal G1/G2	G1, S, G2, M	S, M only (no gaps)	G1, S, G2, M	G1, S, G2, M (+ D-type cyclins for sucrose)	G1, S, G2, M (often shortened G1)
CDK	(none — DnaA-driven)	Cdc28 (single)	CDK1, CDK2	CDK1, 2, 4, 6	CDKA, CDKB plant-specific	Frequently amplified CDK4/6
Restriction point	n/a	START	Skipped	Rb-controlled	Rb-related (RBR)	Often defective (Rb loss)
Cytokinesis	FtsZ Z-ring	Asymmetric bud	Cleavage furrow	Actin-myosin furrow	Cell plate, phragmoplast	Variable; often abnormal
Genome stability	Single chromosome	Diploid, 16 chrs	2N → 2N	Diploid, 46 chrs	Diploid + endopolyploidy	Aneuploid, unstable
Quiescence	Stationary phase	G0 (stationary)	None	G0 (most adult cells)	G0 in dormant buds	Rare — cycle continuously

Real numbers

• Adult human body: ~25 million cell divisions per second.
• Skin epidermis renews fully every ~28 days; intestinal epithelium every ~5 days.
• Hayflick limit: ~50–60 divisions before fibroblasts senesce — driven by telomere shortening.
• p53 is mutated in ~50% of all human cancers — the most commonly mutated oncology gene.
• Cyclin D1 amplified in ~50% of breast cancers, ~30% of mantle cell lymphomas.
• CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib) extend median PFS in HR+ metastatic breast cancer from ~14 to ~24 months on top of endocrine therapy.

Variants and drugs

• Endoreplication — DNA copies without mitosis (Drosophila salivary glands, many plant cells become polyploid).
• Embryonic cleavage cycles — alternating S and M only, ~30 min/cycle off maternal stockpiles.
• Meiosis — one S phase + two M phases (I, II) for haploid gametes.
• Senescence — irreversible exit driven by p16, telomere shortening, or oncogenic stress.
• Drugs: palbociclib (CDK4/6); nutlin (MDM2 → p53 stabilizer); taxol (spindle); vincristine (microtubules); etoposide (topo II → G2 arrest); methotrexate (thymidylate starvation in S).

Common misconceptions

• "M phase is the cell cycle." M is ~4% of cycle time; the rest is interphase.
• "Checkpoints are scheduled transitions." They're damage-response brakes, not clock ticks.
• "Cyclins activate CDKs." Required, but full activation also needs CAK phosphorylation and CDC25 dephosphorylation.
• "All cells cycle constantly." Most adult cells sit in G0; neurons typically never re-enter once mature.
• "Cancer cells divide faster." Often false — they cycle at normal speed but skip checkpoints, accumulate mutations, and refuse to die. Chemo kills any cycling cell, not just fast ones.
• "Cell cycle = mitosis." Mitosis is one phase. The cycle includes interphase, where DNA replication and growth happen.