8a Unit Flow of Genetic Information:
Cellular Reproduction
cell division in prokaryotes: binary fission
cell division in eukaryotes
meiosis vs mitosis
stages of the cell cycle
chromosomes and DNA packaging
interphase: G1, S, G2
M-phase (mitosis): pro, meta, ana, telo
cytokinesis, animals vs plants
G0
control of the cell cycle
cyclins, Cdks
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Cell Theory (from Unit 01)
all organisms consist of one or more cells
the cell is the basic unit of structure for all organisms
added 20 years later:
all cells arise only from pre-existing cells
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Key Concepts
cell division involves an ordinary sequence of events in
which cell duplicates its contents and divides in two
cell cycle
details of cell cycle vary with organism, and different times
in an organisms life
unicellular: generates complete new organism
(bacteria, yeast, protozoa)
metazoans: many cell divisions required to generate new
organism from fertilized egg
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Certain features of cell cycle are universal.
need to faithfully replicate DNA
replicated DNA must be accurately distributed (segregated)
to daughter cells
most cells also duplicate their other macromolecules and
organelles and double in size before they divide
Questions:
How do cells duplicate their contents? (Biol 139)
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How do they partition the duplicated contents and split in two?
Cell Division in Prokaryotes: Binary Fission
origin of replication
replication
of DNA
elongation of cell
septation
inward growth of septum
cell pinches in two
Eukaryotes: Meiosis and Mitosis
meiosis:
division of genetic material to produce daughter cells with
half the hereditary material found in the parent cell
involved only in the production of gametes (eggs and
sperm)
basis of sexual reproduction and genetic inheritance
mitosis
division of genetic material that produces daughter cells
genetically identical to parent cell
usually accompanied by cytokinesis, division of the
cytoplasm into the two daughter cells
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Mitosis / cytokinesis is responsible for key
events in multicellular eukaryotes.
growth & development
wear n tear, wound repair
asexual reproduction
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Phases of the Cell Cycle
M phase alternates with Interphase
Interphase 90% of a proliferating cells time
cell grows by producing proteins and organelles, copies its
chromosomes, and prepares for cell division
subdivisions:
G1 (Gap 1) most of a cells growth
S (synthesis) phase DNA copied
G2 (Gap 2) cell completes preparations for mitosis
M phase mitosis and cytokinesis
subdivided according to state of chromosomes
Eukaryotic Chromosomes
multiple linear chromosomes housed in nucleus
two copies of each essential to survival
highly variable in number
1 pair > 500 pairs
most eukaryotes: 10-50
chromosome # not correlated with complexity!
human 2n = 46, silkworm 56, chickens 78
complex packaging of DNA
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Chromosomal Number in Mammals
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source: Encyclopedia of Life Sciences, Wiley & Sons, 2007
(via Guelph library available on request)
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chromosome size / number versus genome size
Chinese muntjac (2n = 46)
Indian muntjac (2n = 6)
DNA Packing in Eukaryotes
DNA double helix wrapped around histone proteins
tightly packed DNA w/ histones
chromosome in extended form
(mostly like this in cell)
condensation in preparation for mitosis
entire mitotic chromosome
(DNA molecule compacted 10,000-fold)
Homologous Chromosomes vs Sister Chromatids
replicated homolog
(considered one chromosome
consisting of two sister chromatids)
homologs (one from each parent)
Karyotype
Interphase: preparing for mitosis
G1 most of cells growth
S replication of chromosomes
remain attached at centromeres
still fully extended
G2 chromosome condensation
start to form apparatus to move chromosomes around
replication of centrioles
synthesis of lots of tubulin (why?)
when chromosomes condense enough to become visible ...
Overview of Mitosis
G1
parent cell:
4 unreplicated
chromosomes
Fig 11.7
S PHASE AND G2
MITOSIS
sister
parent cell: chromatids
replicated
4 replicated
chromosomes
chromosomes
highly condensed
sister chromatids
separate;
two daughter cells
formed by cytokinesis
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Stages of Mitosis - 1
G2 of interphase
prophase prometaphase
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Metaphase Chromosome
chromatid
kinetochore
microtubules
centromere
chromosome
Stages of Mitosis - 2
metaphase
chromosomes migrate
to equator of cell
(metaphase plate)
anaphase
telophase & cytokinesis
sister chromatids separate
nuclear envelope re-forms;
spindle apparatus disintegrates
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Cytokinesis: Animal vs Plant Cells
- involves ring of actin filaments
just under plasma membrane, in
association with motor proteins
(myosin)
cleavage furrow
- microtubules and proteins define
and organize the regions where new
cell membrane and wall will form
- vesicle from Golgi arrive, carrying
cell membrane and wall components
cell
plate
Fig 11.9
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Cytokinesis in Plant Cells
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Control of the Cell Cycle
cell-cycle length varies greatly cell among types
G1 phase can be eliminated in rapidly dividing cells
non-dividing cells stuck in G1 phase (G0)
rate of cell division can also respond to changes in
environmental conditions
suggests that cell cycle is regulated
factor discovered in mammalian cells that induced mitosis
subsequently shown to induce mitosis in all eukaryotic
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cells (frog eggs, yeast, )
MPF: Heterodimeric Protein
cyclin-dependent kinase (Cdk) catalytic subunit, transfers
phosphate from ATP to certain AAs on target proteins
but not active unless bound to cyclin partner
levels are constant
activated MPF subunit
cyclin regulatory(M-Cdk)
Phosphorylate chromosomal
proteins; initiate M phase
levels oscillate throughout cell cycle Phosphorylate nuclear
P
Cyclin
Cdk
lamins; initiate nuclear
envelope breakdown
Phosphorylate microtubuleassociated proteins. Activate
mitotic spindle?
Fig 11.14b
Phosphorylate an enzyme
that degrades cyclin; cyclin
concentrations decline
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Rise and Fall of M-Cdk Activity through Cell Cycle
imilar to Fig 11.14a
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Four Main Classes of Cyclins drive the
Vertebrate Cell Cycle
Complex
Phase of Cycle
help with passage through restriction
point
G1/S-Cdk commit cells to DNA replication
G1-Cdk
S-Cdk
M-Cdk
carry out
replication
promote events of mitosis
Regulation of Mammalian Cell Cycle by Cyclins
M-Cdk
restriction
point
G1-Cdk
S-Cdk
ig 13.29 Lodish et al.
G1/S-Cdk
Do cells go through the cycle continuously?
depends on cell type, developmental stage, etc
some cells divide continuously at high rate
epithelial linings of intestine
some cells divide very slowly (if all all), but can be induced
to re-enter cell cycle (eg liver cells)
some cells become highly specialized and can no longer
divide
neurons, muscle cells, red blood cells
Cells can opt out of the cell cycle.
G0 PHASE
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Is the cell cycle always the same length?
depends on organism and cell type within organism
mammals:
crypt cells in intestinal lining several times per day
liver cells - few times per year
early embryos divide more quickly
invertebrate 20-30 minutes
mammalian ~13 hours
G1 is most variable phase
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How does the cell decide whether to proceed
through the cell cycle?
Should I divide?
Is my DNA OK to replicate?
Am I ready for mitosis?
Is my DNA properly replicated?
Am I ready to complete mitosis? Are all my chromosomes
1. G1 / S checkpoint
properly attached to or Start)
(Restriction Point spindles?
3
2
2.
G2 / M checkpoint
3.
spindle checkpoint
Restriction Point
1
G1/S Checkpoint: Restriction Point
discovered in yeast (called START)
integration of external and internal signals
size of cell large enough to split into two
DNA undamaged
nutritional state of cell
external signal molecules
normal cells depend on signals from growth factors or
mitogens to trigger cell division
no signal to divide should stay in G0
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G2/M Checkpoint
discovered in frog eggs
checking for internal issues:
DNA properly replicated? undamaged?
activated MPF present?
Spindle Checkpoint (metaphase anaphase)
all chromosomes at metaphase plate, all aligned, all
attached to mitotic spindle?
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Nobel Prize 2001: Key regulators of the cell cycle
Leland Hartwell
START gene, checkpoint concept (yeast)
Tim Hunt
discovery of cyclins (sea urchins)
(Sir) Paul Nurse
What if the answer to any of these questions is NO?
no signal to divide?
stay in G0
DNA damage detected?
halt cycle
fix it or induce cell death
issues with spindles?
halt mitosis and fix
metaphase arrest
- cell division in the absence of signals
- inappropriate start signals
- failure to induce death of damaged cell
- division with DNA damage
features of
cancer
Cell Cycle: Brakes
tumor suppressors: link cell cycle to DNA damage
proteins that detect DNA damage and initiate events that halt
the cell cycle
typically transcription factors that drive expression of genes
that code for proteins that inhibit Cdks
eg: p53 detects DNA damage at G1/S checkpoint
leads to synthesis of inhibitor of G1-Cdk and S-Cdk
Is defective p53 associated with cancer?
loss of p53 (both copies) found in 70% of colon cancers, 30
50% of breast cancers, 50% of lung cancers,
Cell Cycle: Accelerators
if growth factor pathway gets permanently stuck on, cell
division is no longer controlled
can be due to:
over-expression of growth factors
mutations in growth factors, their receptors or any
molecules in downstream pathway
oncogene (oncoprotein):
mutated versions of normal genes/ proteins involved in
driving cell division
Cancer and the Cell Cycle
tumors form when one or more cells in a multicellular organism
begin uncontrolled division
benign tumors are noninvasive and noncancerous
malignant tumors are invasive
spread throughout the body via the blood or lymph, and
initiate secondary tumors
detachment from original tumor and invasion of other
tissues metastasis
cancer initiates as a failure to respect cell cycle checkpoints
particularly G1/S checkpoint
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