Premed · Premed · General Biology 1
Lecture 15: The Cell Cycle and Mitosis
General Biology I — Molecular & Cellular
Learning Objectives
By the end of this lecture, students will be able to:
- Describe the phases of the cell cycle (G1, S, G2, M) and the events occurring in each
- Explain how the cell cycle is regulated by cyclins, CDKs, and checkpoints
- Describe the stages of mitosis and the events in each stage
- Explain the process of cytokinesis in animal and plant cells
- Describe the consequences of cell cycle dysregulation (cancer)
Lecture Content
I. Overview of the Cell Cycle
The cell cycle is the ordered sequence of events that spans from one cell division to the next, ensuring that genetic information is faithfully duplicated and distributed to daughter cells. It consists of two major phases: interphase, during which the cell grows and replicates its DNA (occupying roughly 90% of the total cycle time), and the mitotic (M) phase, during which the cell divides (about 10% of the cycle). The duration varies enormously by cell type: rapidly dividing intestinal epithelial cells complete a cycle in approximately 24 hours, liver cells may take a year or more, and fully differentiated cells such as neurons typically exit the cycle altogether.
II. Interphase
G1 phase (Gap 1) is the main growth period. The cell increases in size, synthesizes proteins and organelles, and carries out its specialized functions. Near the end of G1, the cell faces a critical decision: to commit to another round of division or to exit the cycle and enter G0, a quiescent state in which the cell remains metabolically active but is not preparing to divide. Some cells, such as neurons and mature muscle fibers, reside in G0 permanently. Others, like liver cells, can be stimulated to re-enter G1 in response to tissue damage. In mammalian cells, the restriction point (R) marks the point in late G1 beyond which the cell is committed to entering S phase regardless of external growth signals.
S phase (Synthesis) is when DNA replication occurs. Each chromosome is precisely duplicated, producing sister chromatids that remain joined at the centromere by cohesin proteins. Centrosome duplication also begins during S phase. This period typically lasts 6 to 8 hours in a mammalian cell.
G2 phase (Gap 2) is a final preparation period. The cell continues to grow and synthesize proteins needed for chromosome condensation and spindle formation. DNA replication errors are detected and repaired. Centrosome maturation is completed, readying the cell for entry into mitosis.
III. Cell Cycle Regulation
The cell cycle is driven by cyclin-dependent kinases (CDKs), kinases that are catalytically active only when bound to their regulatory subunit proteins, the cyclins. Cyclin concentrations rise and fall in a predictable, cyclical pattern throughout the cell cycle, activating their CDK partners at the appropriate time. G1/S-CDK (CDK2-Cyclin E) triggers entry into S phase. S-CDK (CDK2-Cyclin A) drives DNA replication. M-CDK (CDK1-Cyclin B), also known as MPF (maturation-promoting factor), triggers entry into mitosis by phosphorylating targets involved in nuclear envelope breakdown, chromosome condensation, and spindle assembly.
Checkpoints
Three major checkpoints ensure that critical events are completed correctly before the cell advances. The G1 checkpoint (restriction point) evaluates cell size, nutrient availability, growth factor signals, and DNA integrity. If DNA damage is detected, the tumor suppressor protein p53 activates the CDK inhibitor p21, halting the cell cycle to allow repair. If conditions are unfavorable, the cell exits to G0. The G2 checkpoint verifies that DNA replication is complete and that any damage has been repaired before the cell enters mitosis. The spindle assembly checkpoint (during metaphase) ensures that all chromosomes are properly attached to spindle microtubules at their kinetochores before sister chromatid separation is permitted. This checkpoint inhibits the anaphase-promoting complex (APC/C) until every chromosome achieves bipolar attachment.
Tumor Suppressors
p53, often called the "guardian of the genome," is activated by DNA damage and can induce cell cycle arrest (via p21), stimulate DNA repair, or trigger apoptosis if the damage is irreparable. Mutations in p53 are found in over 50% of all human cancers. Rb (retinoblastoma protein) controls the G1/S transition: in its unphosphorylated form, Rb sequesters E2F transcription factors, preventing them from activating genes needed for S phase entry. When CDKs phosphorylate Rb, E2F is released and S phase genes are transcribed.
<image>A circular diagram of the cell cycle with G1, S, G2, and M phases marked. Three checkpoint gates are shown: G1 checkpoint (between G1 and S, checking for cell size, DNA damage, and growth signals), G2 checkpoint (between G2 and M, checking for DNA replication completion and damage), and the spindle assembly checkpoint (during M phase). Around the circle, cyclin levels are graphed: Cyclin D rises in G1, Cyclin E peaks at G1/S transition, Cyclin A rises through S and G2, and Cyclin B peaks during M phase. CDK-cyclin complexes are labeled at their respective phases. Arrows from p53 show activation of p21 (CDK inhibitor) in response to DNA damage.</image>
IV. Mitosis
Mitosis is the division of the nucleus into two genetically identical daughter nuclei. Although it is a continuous process, it is conventionally divided into stages for clarity.
During prophase, chromatin condenses into visible chromosomes, each consisting of two sister chromatids joined at the centromere. The mitotic spindle begins to form as centrosomes migrate toward opposite poles of the cell, and the nucleolus disappears. In prometaphase, the nuclear envelope breaks down (triggered by M-CDK phosphorylation of nuclear lamins), and spindle microtubules attach to the kinetochores--protein structures assembled at the centromere of each sister chromatid. Three types of spindle microtubules are at work: kinetochore microtubules connect chromosomes to the poles, interpolar microtubules from opposite poles overlap at the cell midzone, and astral microtubules radiate from centrosomes toward the cell cortex.
At metaphase, all chromosomes are aligned along the metaphase plate, an imaginary plane equidistant from the two poles. Each chromosome is attached to microtubules from both poles (bipolar attachment), and the spindle assembly checkpoint verifies that every kinetochore is properly connected before allowing the cell to proceed.
Anaphase occurs in two overlapping sub-stages. In anaphase A, the APC/C ubiquitinates securin, releasing the protease separase, which cleaves the cohesin proteins holding sister chromatids together. The separated chromatids--now individual chromosomes--move toward opposite poles as kinetochore microtubules shorten by depolymerizing at the kinetochore end. In anaphase B, the spindle itself elongates: interpolar microtubules slide apart (driven by kinesin motors) and astral microtubules pull the poles outward (driven by dynein motors anchored at the cell cortex). The result is one complete set of chromosomes at each pole.
During telophase, the chromosomes decondense back into diffuse chromatin, nuclear envelopes re-form around each set of chromosomes (as lamins are dephosphorylated), nucleoli reappear, and the mitotic spindle disassembles.
<image>A series of six panels showing the stages of mitosis in an animal cell with 4 chromosomes (2n=4). Panel 1 (Prophase): Condensed chromosomes visible as X-shapes, centrosomes at opposite sides with forming spindle, nucleolus fading. Panel 2 (Prometaphase): Nuclear envelope fragments, spindle microtubules attach to kinetochores, chromosomes moving. Panel 3 (Metaphase): All chromosomes aligned at the metaphase plate, kinetochore microtubules from both poles attached. Panel 4 (Anaphase): Sister chromatids separating, moving to opposite poles, cell elongating. Panel 5 (Telophase): Chromosomes decondensing at each pole, nuclear envelopes re-forming, cleavage furrow beginning. Panel 6 (Cytokinesis): Two daughter cells, each with a complete set of chromosomes.</image>
V. Cytokinesis
Cytokinesis, the division of the cytoplasm, typically overlaps with telophase and differs between animal and plant cells. In animal cells, a cleavage furrow forms at the cell equator as a contractile ring of actin and myosin II filaments assembles beneath the plasma membrane. Signaled by the RhoA GTPase, the ring contracts progressively, constricting the cell like a drawstring until it pinches into two daughter cells. The midbody--a remnant of the spindle midzone--is the last bridge between the separating cells before final abscission.
In plant cells, the rigid cell wall prevents furrow formation. Instead, a cell plate forms at the center of the cell and grows outward. Golgi-derived vesicles carrying cell wall materials (pectins, hemicelluloses) converge at the midplane, fuse with one another, and eventually merge with the existing plasma membrane and cell wall to complete the partition. Plasmodesmata--the channels connecting adjacent plant cells--are established during cell plate formation.
VI. Cancer and Cell Cycle Dysregulation
Cancer is fundamentally a disease of uncontrolled cell division caused by the accumulation of mutations in genes that regulate the cell cycle. Proto-oncogenes are normal genes encoding proteins that promote cell growth and division--growth factors, receptors, signaling kinases, and transcription factors. When mutated, they become oncogenes--constitutively active versions that drive proliferation regardless of normal regulatory signals. Because a single mutant allele is sufficient (gain-of-function), oncogene mutations are dominant. Examples include Ras, Myc, HER2, cyclin D, and CDK4.
Tumor suppressor genes encode proteins that normally restrain cell division or promote apoptosis. When both copies are inactivated (loss-of-function mutations, following Knudson's "two-hit hypothesis"), the brakes on the cell cycle are lost. p53, Rb, APC, and BRCA1/2 are prominent tumor suppressors. The hallmarks of cancer--sustained proliferative signaling, evasion of growth suppressors, resistance to apoptosis, unlimited replicative potential, angiogenesis, and invasion and metastasis--reflect the cumulative effect of multiple mutations, consistent with the multi-step model of carcinogenesis.
