Cell Cycle

6.1: The Genome

Cell Cycle & Continuity of Life

• Cell cycle: orderly sequence of events in a cell’s life

  • Starts with division of a parent cell

  • Ends with two daughter cells

  • These then divide in subsequent cycles

• Conserved mechanism across eukaryotes: protists, plants, animals follow similar steps

Genomic DNA

Genome Definition

• Genome: entire DNA content of a cell

Prokaryotic Genome

• Composed of single, circular double-stranded DNA

• DNA located in nucleoid region (no membrane)

• May contain plasmids:

  • Smaller DNA loops

  • Not essential for normal growth

Eukaryotic Genome

• DNA organized in multiple linear, double-stranded molecules

• DNA + proteins = chromosomes

• Species-specific chromosome number

  • Humans: 46 chromosomes in somatic cells

    • Somatic = diploid (2n), 2 matched chromosome sets

    • n = one chromosome set

  • Gametes (sex cells): haploid (n), 23 chromosomes

Chromosomes & Homologous Pairs

• Chromosomes occur in homologous pairs in diploid organisms

  • Homologous = chromosomes that are the same length, contain the same gene loci, and are similar in structure and function

  • One chromosome from each parent

  • Genes may differ in sequence (allelic variation)

Genes & Traits

• Genes = functional chromosome units

  • Code for specific proteins

  • Determine characteristics

• Traits = different forms of characteristics

  • e.g., earlobe shape → free or attached

Genetic Variation

• Caused by different gene versions from each parent

• Example: blood type

  • 3 possible gene sequences: A, B, O

  • Individuals have 2 alleles: AA, BB, OO, or AB

• Diploid human cells: 2 copies of each gene

• Contributes to natural variation (eye color, height, etc.)

Sex Chromosomes Exception

• X and Y chromosomes not fully homologous

  • Only small homologous region (needed for gamete production)

  • Most genes on X ≠ Y

6.2: The Cell Cycle

Cell Cycle Overview

• Ordered series of events → cell growth + division → forms 2 genetically identical daughter cells

• Two main phases:

  • Interphase: cell grows, DNA replicates

  • Mitotic Phase: replicated DNA & cytoplasmic contents separated; cell divides

Interphase

• Normal cell processes + preparation for division

• Subdivided into:

  • G1 (First Gap)

    • Cell increases biosynthesis

    • Accumulates:

      • DNA building blocks

      • Associated proteins

      • Energy reserves for DNA replication

  • S (Synthesis Phase)

    • DNA replication: forms sister chromatids

      • Sister chromatids: two identical DNA copies joined at centromere

    • Chromosomes now duplicated

    • Centrosome duplicates

      • Centrosome = microtubule-organizing center

      • In animals: contains centrioles (rod-like structures at right angles)

      • Plants/fungi: no centrioles

    • Centrosomes later form mitotic spindle (for chromosome movement in mitosis)

  • G2 (Second Gap)

    • Cell replenishes energy

    • Synthesizes proteins needed for chromosome manipulation

    • Organelles duplicated

    • Cytoskeleton dismantled for spindle formation

    • Final prep before mitosis

G0 Phase

• Some cells exit cell cycle and enter G0 (quiescent, non-dividing stage)

• May re-enter G1 if triggered

• Permanent G0: mature nerve and cardiac muscle cells

Mitotic Phase

• Two parts:

  1. Mitosis: division of nucleus (5 stages)

  2. Cytokinesis: division of cytoplasm

Mitosis (Nuclear Division)

5 Phases:

1. Prophase

   • Chromosomes condense → visible under microscope

   • Spindle fibers emerge from centrosomes

   • Nuclear envelope breaks down

   • Golgi & ER fragment/disperse

   • Nucleolus disappears

   • Centrosomes move to opposite poles

2. Prometaphase

   • Chromosomes condense further

   • Nuclear envelope fully disappears

   • Kinetochores form at centromeres

     • Kinetochore = protein structure for spindle attachment

   • Spindle microtubules attach to kinetochores

3. Metaphase

   • Chromosomes align at the metaphase plate (cell equator)

   • Sister chromatids still connected

   • Chromosomes maximally condensed

4. Anaphase

   • Centromeres split, separating sister chromatids

   • Now called chromosomes

   • Move toward opposite poles

   • Cell elongates (non-kinetochore microtubules lengthen)

5. Telophase

   • Chromosomes arrive at poles

   • Chromosomes decondense

   • Nuclear envelopes re-form

   • Spindle breaks down

   • Organelles reassemble

Cytokinesis (Cytoplasmic Division)

• Animals:

  • Begins during anaphase

  • Cleavage furrow forms at metaphase plate

  • Created by contractile ring (actin filaments)

  • Ring contracts → furrow deepens → cell splits in two

• Plants:

  • No cleavage furrow (due to rigid cell wall)

  • During telophase, Golgi vesicles accumulate at metaphase plate

  • Vesicles fuse → form cell plate

  • Cell plate grows outward until it merges with cell wall

  • Vesicle contents form new cell wall (cellulose)

  • Vesicle membranes become new plasma membranes

Correct Order of Mitosis Events (Answer to MCQ):

Correct sequence:

1. Kinetochore attaches to spindle

2. Sister chromatids align at metaphase plate

3. Sister chromatids separate

4. Nucleus reforms & cell divides

Cell Cycle Control & Regulation

Overview

• Timing varies by cell type:

  • Fast-dividing cells: ~24 hrs (e.g., epithelial cells)

  • Non-dividing cells: permanent G0 (e.g., neurons)

• Cell cycle regulated by internal and external factors

Checkpoints

Purpose: Ensure accuracy; prevent damaged or incomplete cells from dividing

1. G1 Checkpoint (Restriction Point)

• Cell commits to division

• Checks:

  • Nutrient availability

  • Cell size

  • DNA damage

• Failure → cell does not enter S phase

2. G2 Checkpoint

• Entry to mitosis blocked if:

  • DNA replication incomplete

  • DNA is damaged

  • Inadequate cell size/proteins

3. M (Spindle) Checkpoint

• Occurs near end of metaphase

• Ensures:

  • All sister chromatids correctly attached to spindle fibers

  • Kinetochores anchored to opposite poles

• Prevents premature entry into anaphase

Defined Terms

• Genome: full DNA content of a cell

• Chromatid: one copy of a duplicated chromosome

• Sister chromatids: identical chromatids joined at centromere

• Centrosome: microtubule-organizing center; forms spindle

• Centriole: rod-like structure in animal centrosomes (not in plants/fungi)

• Kinetochore: protein complex at centromere; attachment site for spindle

• Metaphase plate: central plane where chromosomes align during metaphase

• Cleavage furrow: indentation formed during animal cell cytokinesis

• Cell plate: plant cell structure that becomes the new cell wall during cytokinesis

• G0 phase: non-dividing, resting state outside the active cycle

6.3: Cancer and the Cell Cycle

Cancer and the Cell Cycle

Definition of Cancer

• Cancer = group of diseases caused by uncontrolled cell division

• Despite multiple levels of cell-cycle control, errors still occur

Mutation and Cancer Development

• Mutation = permanent change in DNA nucleotide sequence

• S phase: proper DNA replication is a critical checkpoint

• Even functional control systems allow some replication errors

• If a mutation occurs within a gene → results in a gene mutation

• Cancer begins when a gene mutation leads to production of a faulty protein involved in cell reproduction

Consequences of Mutation

• Faulty protein → minor change in cell → can enable further errors

• Uncorrected mutations accumulate:

  • Passed from parent cell to daughter cells

  • Result in more non-functional proteins

• Over time:

  • Repair and control mechanisms weaken

  • Cell cycle speeds up

  • Uncontrolled cell growth outpaces normal cell growth

  • Can lead to formation of a tumor

Proto-oncogenes and Oncogenes

Proto-oncogenes

• Definition: genes coding for positive cell-cycle regulators

• Normal function: promote progression through the cell cycle

Oncogenes

• Definition: mutated proto-oncogenes that cause cancerous growth

• Mutation can result in:

  • Increased activity of a positive regulator

  • Premature progression through checkpoints

Example: Cdk (Cyclin-dependent kinase)

• Mutation → early activation of Cdk

• May push the cell past checkpoints before readiness

• If resulting daughter cells are too damaged to divide further → mutation not propagated

• If damaged daughter cells can still divide → more mutations accumulate

Key Point

• Any gene that increases cell-cycle rate upon mutation = oncogene

Tumor Suppressor Genes

Definition

• Genes coding for negative regulator proteins

• Negative regulators prevent uncontrolled division

• Act as "roadblocks" to cell-cycle progression until conditions are met

Major Tumor Suppressor Genes

1. RB1 (Retinoblastoma protein)

2. p53

3. p21

Function

• Halt cell cycle to:

  • Allow DNA repair

  • Prevent division if errors are present

  • Trigger cell death (apoptosis) if DNA damage is irreparable

p53 – Key Tumor Suppressor

• Mutated in >50% of human cancers

• Plays multiple roles at the G1 checkpoint

p53 Functions:

1. Activates genes to:

   • Halt the cell cycle

   • Participate in DNA repair

1. If DNA is beyond repair → initiates cell death

Damaged p53 Consequences

• Cell proceeds through the cycle as if no mutations exist

• Mutation gets passed on

• Leads to further mutation accumulation

• Damaged p53 also fails to initiate apoptosis

Defined Terms

• Mutation: permanent change in DNA sequence

• Proto-oncogene: normal gene that promotes cell cycle progression; becomes oncogene if mutated

• Oncogene: mutated proto-oncogene that increases risk of cancer

• Tumor suppressor gene: gene that codes for proteins halting or slowing the cell cycle

• Apoptosis: programmed cell death

• Cdk (Cyclin-dependent kinase): enzyme that regulates cell cycle progression when activated by cyclins

6.4: Prokaryotic Cell Division

Cell Division in Prokaryotes and Eukaryotes

Overview

• Cell division = essential for reproduction in unicellular organisms (e.g., bacteria)

• Both prokaryotic and eukaryotic cells produce genetically identical daughter cells

• In unicellular organisms, daughter cells = new individuals

Requirements for Cell Division

1. Genomic DNA must be:

   • Replicated

   • Properly allocated into daughter cells

2. Cytoplasmic contents must be divided:

   • Ensures each daughter cell has tools to sustain life

Binary Fission (Prokaryotic Cell Division)

Definition

• Type of asexual reproduction in prokaryotes

• Simpler and faster than mitosis

• No nucleus or multiple chromosomes → no mitosis required

DNA Structure in Prokaryotes

• Single, circular DNA chromosome

• Located in nucleoid region (not membrane-bound)

• Associated with packing proteins (similar in function to eukaryotic chromosome proteins)

Steps of Binary Fission

1. Replication starts at the origin (near plasma membrane)

2. Bidirectional replication:

   • Proceeds in both directions from the origin

1. As DNA replicates:

   • Origin points move apart to opposite ends

   • Cell elongates

   • Membrane growth helps move chromosomes

2. Once chromosomes clear the midpoint:

   • Septum formation begins

   • Septum forms from outside in (periphery to center)

1. New cell wall forms

   • Two genetically identical daughter cells result

Role of FtsZ in Prokaryotic Cytokinesis

FtsZ Protein

• Key protein in prokaryotic cytokinesis

• Forms a ring at cell midpoint (site of division)

• Directs septum formation between nucleoids

• Recruits:

  • Cell wall material

  • Membrane material

Comparison to Eukaryotes

• FtsZ is structurally/functionally similar to tubulin (eukaryotic protein)

• Both FtsZ and tubulin:

  • Form rings, filaments, and 3D structures

  • Use GTP (guanosine triphosphate) for assembly/disassembly

Evolutionary Insight

• Homology: structures derived from same evolutionary origin

  • FtsZ is likely ancestral protein to tubulin

• Shows link between prokaryotic division and eukaryotic mitosis

Comparison of Cell Division Across Organisms

Defined Terms

• Binary Fission: asexual reproduction in prokaryotes producing identical daughter cells

• Nucleoid: region in prokaryotic cell where DNA is located (not membrane-bound)

• Septum: dividing wall between two new cells during cytokinesis

• FtsZ: protein in prokaryotes that assembles into ring for cytokinesis; homologous to tubulin

• Tubulin: eukaryotic protein forming microtubules, mitotic spindles, and cytoskeleton

• GTP (guanosine triphosphate): energy molecule used for protein assembly (e.g., FtsZ, tubulin)

• Homology: shared evolutionary origin of structures or genes

• Cleavage Furrow: indentation that begins the process of cytokinesis in animal cells

• Microfilaments: actin-based structures involved in forming cleavage furrow

• Centrioles: cylindrical structures in animal cells from which spindle fibers originate

7.1:

Sexual Reproduction in Eukaryotes

General Info

• Sexual reproduction: Early evolutionary innovation in eukaryotes

• Most eukaryotes reproduce sexually → suggests evolutionary success

• In many animals, it's the only mode of reproduction

Asexual vs. Sexual Reproduction

Advantages of Asexual Reproduction

• Produces genetically identical offspring → advantageous if environment is stable

• No need for a mate → saves energy

• Faster population growth (no males needed; all individuals can reproduce)

• Methods: budding, fragmentation, asexual eggs

• Solitary organisms often retain asexual reproduction

Disadvantages of Sexual Reproduction

• Requires:

  • Finding/attracting a mate

  • More energy expenditure

• Only females produce offspring → slows population growth (sexual reproduction = 2x slower)

• Asexual population could outcompete sexually reproducing population in theory

Why is Sexual Reproduction So Common?

Main Reason: Genetic Variation

• In asexual organisms, variation comes only from mutations

• In sexual organisms:

  • Mutations + recombination during meiosis

  • Meiosis: division of nucleus → reduces chromosome number by half → forms gametes

  • Fertilization: fusion of gametes → restores diploid condition

• Continuous reshuffling of genes allows offspring to adapt to changing environments

Red Queen Hypothesis (Leigh Van Valen, 1973)

Key Idea

• Ongoing variation is needed to maintain survival, not just gain advantage

• Named after Red Queen's race in Through the Looking-Glass:

  • “It takes all the running you can do to stay in the same place”

Coevolution

• Species evolve in response to each other

• Examples:

  • Bats and moths:

    • Bats use echolocation

    • Moths evolve:

      • Simple ears to hear bats

      • Escape behaviors (fly away, drop to ground)

      • Clicking noises to confuse bats

    • Bats evolve quieter clicks to evade moth detection

Implication

• Any advantage (e.g., mutation) leads to counter-adaptations

• Only way to keep up = continual adaptation

• Sexual reproduction enables faster genetic change through variation

Sexual Life Cycles Overview

Basic Pattern

• Meiosis creates haploid gametes (1n)

• Fertilization restores diploid (2n) condition

• Variation introduced:

  • During meiosis

  • During fertilization

Three Main Life Cycle Types

1. Diploid-Dominant Life Cycle (Animals)

• Most animals, including humans

• Multicellular diploid stage is dominant

• Haploid gametes produced via meiosis from diploid germ cells

• Gametes cannot divide again → no multicellular haploid stage

• Fertilization restores diploid state → grows by mitosis

2. Haploid-Dominant Life Cycle (Fungi, Some Algae)

• Multicellular organism is haploid

• Two haploid individuals fuse → diploid zygote

• Zygote undergoes meiosis immediately → forms haploid spores

• Spores grow via mitosis into multicellular haploid individuals

Mutation Scenario: If a fungus can’t produce a minus mating type, it can’t reproduce sexually (requires both + and - types)

3. Alternation of Generations (Plants, Some Algae)

• Both diploid and haploid multicellular stages

  • Haploid = gametophyte → produces gametes by mitosis

  • Fertilization → diploid zygote

  • Zygote grows via mitosis → sporophyte (diploid multicellular plant)

  • Sporophyte produces haploid spores via meiosis

  • Spores grow into gametophytes

Defined Terms

• Sexual reproduction: Union of gametes from two individuals to produce offspring with genetic variation

• Asexual reproduction: Reproduction without gametes; offspring genetically identical to parent

• Diploid (2n): Two sets of chromosomes

• Haploid (1n): One set of chromosomes

• Meiosis: Cell division reducing chromosome number by half; introduces variation

• Fertilization: Fusion of two haploid gametes to restore diploid state

• Gamete: Haploid sex cell (egg or sperm)

• Germ cell: Specialized diploid cell that undergoes meiosis to form gametes

• Spore: Haploid cell that can develop into a haploid organism without fertilization

• Gametophyte: Haploid multicellular organism that produces gametes

• Sporophyte: Diploid multicellular organism that produces spores

• Coevolution: Reciprocal evolutionary changes between interacting species

• Red Queen Hypothesis: Evolutionary theory stating species must constantly evolve to survive against ever-evolving opponents

7.2: Meiosis

Overview of Sexual Reproduction & Meiosis

Fertilization & Ploidy

• Fertilization: Union of 2 haploid cells → results in diploid cell (2 sets of chromosomes)

• Ploidy: Number of chromosome sets in a cell

  • Haploid (n): 1 set

  • Diploid (2n): 2 sets

Without reduction of chromosome number, fertilization each generation would double the ploidy

• Meiosis: Nuclear division that reduces chromosome number from diploid to haploid

Chromosome Basics

Somatic Cells (Body Cells)

• Diploid (2n)

• Contain homologous chromosomes (1 from each parent)

• Homologous chromosomes: Same genes, same locations, may differ in versions (alleles)

Gametes (Sex Cells)

• Haploid (n)

• Only contain 1 copy of each homologous chromosome

• Fuse in fertilization to restore diploid state

Mitosis vs Meiosis

Mitosis

• 1 nuclear division → 2 genetically identical, diploid daughter cells

• Functions in: Growth, repair, some asexual reproduction

Meiosis

• 2 nuclear divisions → 4 genetically unique, haploid cells

• Functions in: Sexual reproduction

• Differences occur primarily in Meiosis I

Phases of Meiosis

Interphase (Before Meiosis)

• Same as in mitosis:

  • G1 phase: Cell growth

  • S phase: DNA replication

    • Chromosomes duplicate into sister chromatids held by centromere

  • G2 phase: Final preparations

Meiosis I → Reduction Division

Prophase I

• Synapsis: Homologous chromosomes pair tightly

• Crossing Over: Exchange of segments between non-sister chromatids

  • Results in recombinant chromosomes (mix of maternal + paternal DNA)

  • Occurs at chiasmata

• Homologous chromosomes form tetrads (4 chromatids)

First source of genetic variation: Crossing over

Prometaphase I

• Spindle fibers attach to kinetochores on homologous chromosomes

• Nuclear envelope breaks down

• Each tetrad attaches to microtubules from both poles

Metaphase I

• Tetrads align at metaphase plate

• Independent assortment: Orientation of homologous pairs is random

Second source of genetic variation

• For n = 23 in humans → 2²³ = 8.4 million possible combinations (not counting crossing over)

Anaphase I

• Homologous chromosomes pulled apart (not sister chromatids)

• Chiasmata connections break

Telophase I & Cytokinesis

• Chromosomes reach poles

• Nuclear envelopes may or may not reform (species dependent)

• Cytokinesis:

  • Cleavage furrow (animals/fungi) or cell plate (plants)

• Each cell is now haploid, but with duplicated sister chromatids

Sister chromatids are not identical due to crossing over

Meiosis II → Separation of Sister Chromatids

No additional DNA replication (no S phase)

• If present, Interkinesis: Brief resting phase between meiosis I and II

Prophase II

• Chromosomes condense (if they had decondensed)

• New spindles form, centrosomes move to poles

• Nuclear envelopes fragment (if present)

Prometaphase II

• Kinetochore forms on each chromatid

• Spindle fibers attach from opposite poles

Metaphase II

• Chromosomes line up at center (similar to mitosis)

Anaphase II

• Sister chromatids pulled apart to opposite poles

Telophase II & Cytokinesis

• Chromosomes decondense

• Nuclear envelopes reform

• Cytokinesis produces 4 haploid cells, each genetically unique

Variability due to:

• Crossover (Prophase I)

• Independent assortment (Metaphase I)

Key Definitions Recap

• Ploidy: Number of sets of chromosomes

• Diploid (2n): Two sets of chromosomes

• Haploid (n): One set of chromosomes

• Homologous chromosomes: Pairs with the same genes from each parent

• Sister chromatids: Identical copies of a chromosome, connected at centromere

• Synapsis: Pairing of homologs in Prophase I

• Chiasmata: Site where crossing over occurs

• Recombinant chromosome: New genetic combo of maternal + paternal DNA

• Independent assortment: Random alignment of homolog pairs during Metaphase I

• Reduction division: Meiosis I, reduces chromosome number by half

Meiosis vs. Mitosis Summary

Final Takeaways

• Meiosis ensures genetic diversity via:

  • Crossing over

  • Independent assortment

• Produces haploid gametes essential for maintaining chromosome number across generations

• Mitosis = growth/repair, Meiosis = sexual reproduction

7.3: Variations in Meiosis

Chromosomal Disorders from Abnormal Meiosis

I. Categories of Chromosome Disorders

1. Abnormalities in Chromosome Number

2. Chromosome Structural Rearrangements

   • Both can affect many genes → usually dramatic, often fatal.

II. Cytogenetics & Karyotyping

• Cytogenetics: study of chromosomes under a microscope.

• Karyotype: visual profile of chromosomes (number, size, banding pattern, centromere position).

• Karyogram: organized visual chart of chromosomes (homologs paired from longest to shortest).

Clinical Use:

• Detects chromosomal abnormalities:

  • Too many/few chromosomes (e.g. Down syndrome, Turner syndrome).

  • Large deletions/insertions (e.g. Jacobsen syndrome → deletion on chromosome 11).

  • Translocations (e.g. chronic myelogenous leukemia).

III. Abnormalities in Chromosome Number

• Most visible via karyogram.

Caused by:

• Nondisjunction: failure of homologous chromosomes (meiosis I) or sister chromatids (meiosis II) to separate.

Outcomes:

• Meiosis I nondisjunction:

  • 2 gametes: n+1

  • 2 gametes: n–1

• Meiosis II nondisjunction:

  • 1 gamete: n+1

  • 1 gamete: n–1

  • 2 normal gametes

Terms:

• Euploid: normal chromosome number (e.g. 46 in humans).

• Aneuploid: abnormal number

  • Monosomy: 1 copy of chromosome (loss)

  • Trisomy: 3 copies (gain)

Examples:

• Down syndrome (Trisomy 21)

  • Extra chromosome 21

  • Physical/cognitive delays

  • Risk increases with maternal age

• Turner syndrome (X0)

  • Female with only one X chromosome

  • Short stature, webbed neck, sterility

• Klinefelter syndrome (XXY)

  • Male with extra X chromosome

  • Small testes, breast development, less body hair

• Triplo-X (XXX)

  • Female, often with developmental delays, reduced fertility

IV. X Inactivation

• In females, one X chromosome randomly condenses into a Barr body early in development.

• Ensures dosage compensation.

• All descendant cells inactivate the same X.

Phenotypic example:

• Tortoiseshell cats: coat color variegation due to random X inactivation → only in females.

V. Polyploidy

• Polyploid: more than two chromosome sets (e.g. triploid = 3n).

  • Rare in animals, common in plants (often larger/more robust).

  • Animals with odd chromosome sets → sterile (meiosis fails).

VI. Structural Chromosomal Rearrangements

1. Duplications

• Segment of chromosome duplicated.

• Can result in gene dosage imbalance.

2. Deletions

• Segment of chromosome missing.

• Cri-du-chat syndrome:

  • Deletion on short arm of chromosome 5

  • Nervous system issues, distinct facial features, cat-like cry

3. Inversions

• Chromosome segment breaks, rotates 180°, re-inserts.

  • Gene order reversed

  • Usually milder than aneuploidy unless genes are disrupted

Evolution Connection:

• Chromosome 18 inversion may have driven human evolution from chimps.

  • Affected gene spacing and expression (e.g. ROCK1 and USP14)

4. Translocations

• Segment of one chromosome moves to nonhomologous chromosome.

  • Reciprocal translocation: segments exchange → no gain/loss of DNA

  • Can be benign or cause cancer, schizophrenia, etc.

Effects depend on:

• Gene disruption or misregulation due to new position.

Summary Definitions

Lecture: Mitosis and Meiosis

• Mitosis: the process where cells replicate their DNA and split to become two identical, diploid, daughter cells.

• Meiosis: the process where a cell reduces its chromosome number by half and splits twice to produce four haploid daughter cells that become either sperm or egg depending on the gender of the organism. Meiosis only occurs in sex cells

• Differentiation: first half of cell division of meiosis-meiosis I- where the number of chromosomes is cut in half