Cell cycle

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The Cell Cycle

The cell cycle is the ordered, self-regulated sequence of events by which a cell duplicates its contents and divides into two genetically identical daughter cells. In rapidly dividing human cells, the full cycle takes about 24 hours. - Junqueira's Basic Histology, p. 167

Overview: Phases of the Cell Cycle

The cycle is divided into two major parts: Interphase (G1, S, G2) and M phase (Mitosis).

Phase	Duration	Key Events
G1 (Gap 1)	~9-25 h	Cell grows; RNA and protein synthesis; response to mitogens; most variable phase
S (Synthesis)	~7.5-10 h	DNA replication; histone synthesis; centrosome duplication begins
G2 (Gap 2)	~3.5-4.5 h	Proteins for mitosis accumulate; proofreading of replicated DNA
M (Mitosis)	~1 h	Chromosome segregation and cell division (prophase, metaphase, anaphase, telophase)
G0	Variable	Quiescent state; cells exit cycle; may re-enter or terminally differentiate

Histology: A Text and Atlas, p. 255; Junqueira's Basic Histology, p. 167-168

Checkpoints

Checkpoints are internal quality-control mechanisms that halt the cycle unless specific conditions are met. - Histology: A Text and Atlas, p. 255

Major Checkpoints

Restriction Checkpoint (late G1, G1/S boundary)
- The "point of no return" - the most important checkpoint in the cell cycle
- The cell evaluates its own replicative potential, nutrient availability, and extracellular signals
- Once passed, the cell is committed to completing division
- Regulated by CDK4/6-Cyclin D complexes phosphorylating RB protein
G1 DNA-Damage Checkpoint
- Monitors integrity of newly replicated DNA
- If DNA is irreparably damaged, p53 levels rise and block entry to S phase
- Cell is diverted to apoptosis or senescence
S DNA-Damage Checkpoint
- Detects DNA damage during replication and stalls replication forks
G2 Checkpoints (two)
- Unreplicated DNA checkpoint: ensures complete DNA replication before mitosis
- G2 DNA-damage checkpoint: monitors for damage acquired during S phase
M Phase Checkpoints (two)
- Spindle-assembly checkpoint: ensures all chromosomes are properly attached to spindle fibers
- Chromosome-segregation checkpoint: ensures equal distribution to daughter cells

Histology: A Text and Atlas, p. 255-260; Robbins & Kumar Basic Pathology, p. 232

Molecular Regulation: Cyclins, CDKs, and CDKIs

The molecular engine of the cell cycle is driven by Cyclin-Dependent Kinases (CDKs) that become active only when bound to their cyclin partner. Cyclins rise and fall in concentration as the cycle progresses - hence the name. - Robbins & Kumar Basic Pathology, p. 232

Key Cyclin-CDK Complexes

Cyclin	CDK	Phase Active	Key Target
Cyclin D	CDK4/6	G1 progression	Phosphorylates RB protein (releases E2F)
Cyclin E	CDK2	G1/S transition (S phase entry)	ATM/ATR kinases, p53
Cyclin A	CDK2	S phase progression	DNA replication machinery (RPA, DNA polymerase)
Cyclin A	CDK1	G2/M entry	Cdc25 phosphatase, Cyclin B
Cyclin B	CDK1	M phase	Chromatin proteins, nuclear lamins, centrosomal proteins

Histology: A Text and Atlas, Table 3.1, p. 260

The RB Protein - Master Brake at G1/S

In early G1, RB (retinoblastoma protein) is in its hypophosphorylated (active) form and suppresses cell cycle progression by binding and inactivating transcription factor E2F. When Cyclin D-CDK4/6 complexes phosphorylate RB, E2F is released and drives transcription of genes needed for S phase entry (including Cyclin E). This creates a positive feedback loop that makes the G1/S transition essentially irreversible. - Robbins & Kumar Basic Pathology, p. 232-233

CDK Inhibitors (CDKIs)

Two families of CDKIs act as molecular brakes:

INK4 family (p15, p16, p18, p19): selectively inhibit Cyclin D-CDK4 and Cyclin D-CDK6
CIP/KIP family (p21, p27, p57): broadly inhibit all CDK complexes

p53 is particularly important - in response to DNA damage, p53 induces transcription of p21, which then inhibits CDK complexes and halts the cycle to allow DNA repair.

G0 - The Quiescent State

Cells that exit the cycle in G1 enter G0. Some cells (hepatocytes, lymphocytes) can return to G1 under appropriate stimuli. Others undergo terminal differentiation (G_TD) and never divide again - most neurons and skeletal muscle cells are examples. - Histology: A Text and Atlas, p. 255

Mitosis - The M Phase

Mitosis itself is subdivided into four stages:

Stage	Events
Prophase (~1 h)	Chromosomes condense; spindle apparatus forms; nuclear envelope breaks down
Metaphase (<1 h)	Chromosomes align at the metaphase plate; kinetochores attach to spindle fibers
Anaphase (<0.5 h)	Sister chromatids pulled to opposite poles
Telophase (minutes)	Nuclear envelopes reform; chromosomes decondense; cytokinesis begins

Clinical Relevance: Cell Cycle Dysregulation in Cancer

The G1/S checkpoint is the one most commonly disabled in human cancers. Two main mechanisms: - Robbins & Kumar Basic Pathology, p. 233

Gain-of-function in CDK4 or D cyclins
- Cyclin D overexpressed in breast, esophageal, liver cancers, lymphomas
- CDK4 amplified in melanomas, sarcomas, glioblastomas
Loss-of-function in CDKIs
- CDKN2A (encoding p16) is deleted or silenced in gliomas, carcinomas, sarcomas, and leukemias
- Germline CDKN2A mutations found in familial melanoma
Loss of RB
- RB mutations disable the G1/S checkpoint directly
- Prototype tumor suppressor; mutated in retinoblastoma, osteosarcoma, and others

This means that essentially all cancers carry some genetic alteration that frees them from normal G1/S checkpoint constraints, allowing continuous re-entry into S phase.

Key summary: The cell cycle is a tightly choreographed G1 → S → G2 → M sequence controlled by cyclin-CDK complexes at each transition. Checkpoints - especially the restriction point at G1/S - sense DNA damage and cellular readiness to prevent defective replication. CDKIs (p16, p21, p27, etc.) and tumor suppressors (RB, p53) are the brakes. Their loss is a hallmark of cancer.

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