about Cell Division, Cell Cycle & Apostosis_Handout

8/11/2019 about Cell Division, Cell Cycle & Apostosis_Handout

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Cell Division,

Apoptosis

Dr. Mrinal K. Maiti / Dr. Pinaki Sar

Dept. of Biotechnology

Cell Cycle


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Animal and Plant Cells Have More Similarities Than Differences

Plant cells have a cell wall,chloroplasts, and a central

vacuole;

but animal cells do not

The centralvacuole may

occupy 90%of a plant cell.

What is Cell Division?

Separation of a single cell into two new cells

Very vital event in all living organisms


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What is cell division cycle or cell cycle?

Orderly sequence of molecular eventsin which

a single cell duplicates its contents and divides

into two identical cells.

This cycle of duplication and divisionis known

as cell cycle or cell division cycle.

An essential mechanism for all living beings to

reproduce and survive.

Why cell division / cell division cycle is so

important in living system?

Cell division must bebalancedby cell growth in a

particular species (critical for unicellular organisms)

Cell division is required to form differenttissues and

organs(critical in multicellular organism)

Control of cell division cycle is vitalto all organisms

Partial or complete loss of normal control on cell

division cycle leads todisease, cancer and death


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The detailed molecular events of cell division cycle varyfrom

organism to organism, and in a single organism it may vary in

time and space

Most fundamental event in cell division cycle of living system

is common:

Duplicationof genetic material/information (DNA) in the parent

cell and

Accurate distribution (segregation)of identical DNA into two

cells of next generation (progeny/daughter cells).

Chromosome:the specially organized thread-like structure of the

gene c ma er a o an organ sm nvo ve n s orage antransmission of the biological information (genes) / inheritance of

traits from parents to offspring.

Genome: the complete genetic information (i.e., total DNA

content) carried by a cell or organism.

Each cell contains chromosomes, and

chromosomes contain genes

~ 1013


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Most of the higher eukaryotes are diploid (2n) i.e. their body

(somatic) cells contain two copies of the basic genome set (two

sets of homologous chromosomes)

Some eukaryotes and the sex cells (gametes) of most higher

eukaryotes are haploid (n) i.e. these cells contain one basic

n + n ----- 2n

Through fertilization of two sex cells (gametes) : one basic

genome set (n) from male gamete or fathers sperm and another

How the 2n genome arises?

se n rom ema e game e or mo er s egg.

How the n genome arises? 2n ----- n + n

By one kind of cell division (meiosis)


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n + n ----- 2n












n + n ----- 2n








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Cell Division

Mitosis (equal division): When the somatic (body) cells just

increase in number.

One cell -------- (genome duplication) -------- Two cells

In eukaryotic organism, two different types of cell divisions occur

n p o --- n --- n + n

n (haploid)---(2n)--- n + n

Meiosis (reduction division) : For sexually reproducing diploidorganism specialized diploid cells (meiocytes) undergo two

sequential nuclear divisions to form four haploid cells.

One cell -------- (genome duplication) -------- Four cells

2n ---(4n)--- (2n) + (2n) ---- n + n+ +n + n

These haploid cells are called gametes (sperms and eggs in plants,

animals) or spores (fungi, algae).


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Mitosis (equal division): When the somatic (body) cells justincrease in number.

One cell -------- (genome duplication) -------- Two cells

In eukaryotic organism, two different types of cell divisions occur

n --- n --- n + n

n ---(2n)--- n + n

Meiosis (reduction division) : For sexually reproducing diploid

organism specialized diploid cells (meiocytes) undergo two

sequential nuclear divisions to form four haploid cells.

One cell -------- (genome duplication) -------- Four cells

2n ---(4n)--- (2n) + (2n) ---- n + n+ +n + n

These haploid cells are called gametes (sperms and eggs in plants,

animals) or spores (fungi, algae).

Meiosis: single round of

chromosome duplication

followed by two rounds of

chromosome segregation.

Unique features of mitosis and meiosis compared

2n 2n

4n 4n

roun e os s-

segregates the homologs

that pair up.

2nd round (Meiosis-II)segregates the sister-

chromatids

2n 2n 4n

Mitosis: homologs do not

pair up and segregate

but the sister-chromatids

segregate

2n 2nn n n n


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Meiosis: single round ofchromosome duplication

followed by two rounds of


Unique features of mitosis and meiosis compared

2n 2n

4n 4n

u -

segregates the homologs

that pair up.

2nd round (Meiosis-II)

segregates the sister-

chromatids

Mitosis: homologs do not

pair up and segregate

but the sister-chromatids

segregate

2n 2nn n n n

Mitosisensures that every cell in a individual carries the

same chromosomes number/ genomic content/biological information. Thus genetically conservative.

Significance of

Meiosis distributes one member of each chromosomepair to each gametes and restores the species-specific

chromosome number/ genomic content/ biological

.

Additionally, it contributes to genetic diversity that

stimulates evolution.


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Cell Cycle(focusing on Mitosis division only)

Essential events in a cell cycle

Cell growth &

duplication

division

Repeating patternof

cell growth (including

Chromosome

segregation

chromosome duplication)

and

cell division (including



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Cell cycle alternates between mitosis (M) and

interphase (G1, S, G2)

~ 0.5

hour

~ 9 hours

~ 4.5

hours

~ 10

hours

environment)

A typical human cell has cell division cycle of 24 hours

(Monitor the environment)

Two major phases

of cell cycle


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Interphase long period of cell cycle

between two divisions. Here cells grow,duplicate chromosomes and prepare for

the division

G1: gap phase birth of cell to the onset

of chromosome du lication the di loid

Phages of cell cyclePhages of cell cyclePhages of cell cycle

2n /

n4n /

2n

.

cells with 2n and haploid cells with n

number of chromosomes)

S: synthesis phase chromosome

duplication due to replication of DNA

G2: gap phase end of chromosome duplication (formation of sister

.

with 2nnumber of chromosomes)

M: mitosis phase nuclear division follows division of cytoplasmic content

(cytokinesis) to separate sister chromatids into daughter cells

G0: resting phase cells exit from cell cycle and survive for days or years

All normal cells undergo complete cell cycle

Different species has different time period for each cell cycle

Cells in different tissues of the same s ecies have different cell

Some features of cell cycle

cycle duration

A typical eukaryotic cell cycle has four phases: G1, S, G2 and M

One critical event i.e., chromosome duplication occurs in S-phase

Another critical event i.e., segregation of duplicated chromosome

occurs in M-phase

M-phase and S-phase are separated by G1-phase and G2 phase,

when various intracellular and extracellular signals monitor the

cell cycle progression


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A typical human cell has cell division cycle of 24 hours: G1 ~ 9 h,

S ~ 10 h, G2 ~ 4.5 h and M ~ 0.5 h

However, cancer cells and embryonic cells skip G1, and G2, so

Some features of cell cycle (Contd..)

All normal cells in an individual do not undergo the cell cycle at

the same time (asynchronous)

A few type of cells withdraw from the cycle of division and

. .

are fully differentiated i.e. eye lens cells and nerve cells)

Cell cycle organization and control/regulation are highly

conserved during evolution from single cell to multicellular

organism

on ro o ce

division cycle


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Cell cycle control system triggers the sequential events

The eukaryotic cell cycle

control system has three

major checkpoints as

surveillance mechanism for

cell cycle progression or

transitions :

i) Start or restriction pointii) G2/M checkpoint

iii) Metaphase/anaphase

Cyclins & cyclin-dependent kinases (Cdks): central

components of the cell cycle control system

Cyclin-Cdk complex consisted of a

regulatory cyclin subunitand acatalytic

cyclin-dependent kinase subunit

Cyclin protein regulates the assembly

and activation of the cyclin-Cdk complex

This activation triggers the sequentialevents for cell cycle progression.

Biochemical switches include

, - ,

activation or inactivation of other

activator or inhibitor proteins,new sets

of gene expression and proteasome-

mediated degradation of proteins


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Different classes of cyclins undergo cyclical synthesis

and degradationleading to activation and de-activation of

cyclin-Cdk complexes

APC/C ubiquitin-ligase

Several key regulators of cell cycle control system are degraded

by cyclical proteolysis mediated by ubiquitin-ligases

APC/C ubiquitin-ligase

SCF ubiquitin-ligase


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Large multisubunit ubiquitin-ligases involved in cell-cycle

controlare:

APC/C (anaphase-promoting complex or cyclosome)

and SCF(skp, cullin, F-box subunits) polyubiquitinylate their

target protein for proteasome-mediated degradation.

The APC/C ubiquitin-ligase helps in degradation of the securin

and M-cyclins, thus induces the anaphase and telophase

progression.

[Securin protein protects the protein linkages that hold the

sister chromatid pairs together in early M-phase].

SCF ubiquitin-ligase helps in degradation of the CKI (Cdkinhibitor) protein at the late G1-phase, thus induces the S-

phase.

[Normally, CKI protein upon binding with cyclin-Cdk complex,

inactivate the later].

Aninteresting theme in the molecular events of cell-cycle control:

In each phase the regulatory molecules activate the steps required

in that particular phase and also prepare the cell for the next phase

of the cell-cycle. Thus, sequential or properly order events/phases

Some features of cell cycle control

are maintained in the cell cycle.

Partial or complete loss of control of cell-cycle (and apoptosis)

may lead todiseased condition or cancer.

In normal cells, the minor damages in DNA are repaired and

sma errors n mo ecu ar even s are correc e . e ce -cyc e

checkpoints delay or arrest the cells to proceed to the next stage

until the DNA damage is repaired or other molecular events of each

phase are completed / corrected before the next step is initiated.


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If the DNA damage can not be repaired or any other faultyevents occurred during any phase of cell cycle, the defective cell

will not complete the division to proliferate, rather the cell death

or apoptosis program will be inducedto eliminate them from the

Some features of cell cycle control (contd..)

normal healthy organism.

Several defects in the cell cycle checkpoints may lead to

abnormal or faulty molecular events, accumulation of multiple

mutations and DNA rearrangements in the genome resulting in

disease or cancer phenotype.

Understanding the detailed control mechanism of cell cycle will

have significant consequences in the treatment of diseases and

cancerby designing suitable drugs and therapeutic strategies.

Apoptosis /

Programmed

Cell Death (PCD)


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Programmed Cell Death/Apoptosis /

Apoptosis (Greek word meaning dropping off or falling off, as

leaves from a tree)is one type ofPCD in which asuicide program

is activatedwithin an animal cell leadin to ra id cell death.

What is it ? or What are the features?

In multicellular organisms (animals and plants),programmed cell

death (PCD)is agenetically controllednatural process by which the

cells kill themselves or commit suicidethrough the activation of a

intracellular death program.

This is an essential and critically important part in the the

organisms growth and development and continues into adulthood or

maturity.

Apoptosis / Programmed Cell Death

Theapoptotic pathway hasthree major components-

Cell membrane-boundreceptors

What is it ? or What are the features? (contd..)

Intracellularregulatory proteins

Effector proteases/ proteolytic enzymes calledcaspases.There are certain morphological and biochemical changesoccur in

the apoptotic cells including formation of membrane-bound bodies

.

In contrast to apoptosis or PCD, the animal cells that die accidentally

in response to an acute injury (e.g. trauma or lack of blood supply) or

pathogen infection by a process calledcell necrosis.


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Component 1

Component 2

Component 3

Apoptotic cells are morphologically different from the normal cells

Theapoptoticcellsshrink, condense, cytoskeleton collapses, most cell

components broken down including condensation of nucleus and

fragmentation of the chromatin/DNA.

Sometimes (if the cells are large), the broken cell components are

re ease as mem rane- oun o es ca e apop o c o es. ecause

the dying cells and the apoptotic bodies are engulfed by the

neighboring cells or macropahges rapidly before they can spill their

contents,there is no inflammatory response in PCD.Necrotic cells swell and

burst, spill their

contents over the

Necrotic cellApoptotic cell

neighboring cells,

leading to the elicitation

of the inflammatory

response unlike the

apoptotic cells.


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Apoptotic cells are biochemically recognizable

Apoptotic cells have characteristics biochemical changes that can beused to identify the PCD.

1.Chromosomal DNA gets fragmented

2. Phosphat dylser ne (a negatively charged phospholipid) which

normally exclusively located in the inner leaflet of lipid bilayer of

plasma membrane,flips to the outer leaflet in apoptotic cells. This

phosphatidylserine, now acts as biochemical marker of the

apoptotic cells.

Due to the phosphatidylserine surface markers, the apoptotic cells

display eat me signals to the neighboring cells andmacrophages which, in turn, phagocytose the dying cells.

Most healthy cells display certain dont eat me signals or

survival signals(calledtrophic factors), so that macrophages do not

engulf any normal cells.

Apoptotic cells are biochemically recognizable (contd..)

Thus, in addition to expressing the eat me signal i.e.

phosphatidylserine surface marker,these apoptotic cells must lose

or inactivate the dont eat me signals or trophic factors.

. e

mitochondria.

(a)Loss of usual electrical potential that exists across of the innermembrane in normal mitochondria.

(b)The proteincytochrome C, normally located in the intermembrane

, .


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PCD/ Apoptosis eliminates unwanted cellsduring organ formation /early development.

Necessities or Functions of PCD / Apoptosis

Digits formation in mouse paw

during embryonic development

Removal of tail as tadpole

changes into a frog

,

very fast and repaired.If the damage is great enough or not repairable,

the cells undergo apoptosis. E.g.DNA damageby various means, if not

immediately repaired, it may lead tocancer-promoting mutation. These

defective cells kill themselves by apoptosis.

PCD/Apoptosis regulates the cell numbers, e.g. in developing

nervous system, number of nerve cells matched/adjusted to the number

of target cells for correct connection/communication.

Necessities or Functions of PCD / Apoptosis (Contd..)

In adult tissues that are neither growing nor shrinking,

PCD/Apoptosis and cell division must be tightly/correctly regulated to

maintain the exact balance.


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PCD/Apoptosis functions as a quality control or vigilant process for

identifying and eliminating cells that are abnormal, nonfunctional or

potentially dangerous to the host.

The PCD/Apoptosis also eliminates most of the lymphocytes that

Necessities or Functions of PCD / Apoptosis (Contd..)

have been activated by the pathogen infection and their function

(destruction of the responsible pathogen)has been completed.

Apoptosis/PCD occurs at a significantly high rate in human bone

marrowwhere most blood cells are produced.

Either excessive or insufficient apoptosis/PCD can contribute

sease, e.g. ear a ac s an s ro es w ere many ce s e y necros sdue to inadequate blood supply but some less affected cells die by

apoptosis.

Complete understanding of the PCD/Apoptosiswill have significant

consequences indesigning suitable drugs for the treatment of diseases.

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about Cell Division, Cell Cycle & Apostosis_Handout