BIOL 2520 - Lecture 5 (Overview of cell cycle)

Third tennet of cell theory

New cells only originate from other living cells. In order to acieve this, the cell cycle is a very important aspect.

Reproduction purpose for single-cells organisms

Reproduction ensures propogation of species

Reproduction for multicellular organisms

1.) 1 cell, specifically a zygote, divides to become a highly organized complex of many cells

2.) Cell division then continues throughout life, with adult humans having millions of cell divisions occurring at any given moment to replace old and/or damage cells.

Cell cyle

The time from one division to the next

2 phases of the cell cycle

1.) M (mitotic) phase: Phase that includes mitosis (nuclear division) and cytokinesis (cell division)

2.) Interphase: The time between one M-phase and the next. It is when the cell grows, metabolizes, and duplicates its DNA.

3 phase of interphase

1.) G1 phase

2.) S phase

3.) G2 phase

Length of Interphase

1.) It varies depending on the cell type

2.) Some only take 30 minutes, such as embryos

3.) Others take 12-36 hours, such as human blood cells

4.) There are even some that take months, such as liver cells

S phase vs. G1 & G2 phase

S-phase: Phase where cell replicates its DNA

G1 & G2 phase: Phase where cell continues to grow

What happens when the cell cycle only has M-phase and no interphase

The cells continue to shrink upon each cell division, since the cells don’t have enough time to grow

Cell categorization with respect to the cell cycle

1.) Cells that do not enter the cell cycle and instead enters a permanent arrest stage, aka G0, until they die.

2.) Cells that do not normally divide but can be induced to, by the right signal

3.) Cells that divide regularly, usually because they’re constantly being damaged and therefore must be replaced

Cells that do not enter the cell cycle ex.)

1.) Neurons

2.) Muscle cells

3.) Red blood cells

Cells that do not normally divide but can be induced to ex.)

1.) Liver cells

2.) Lymphocytes

Cells that divide regularly ex.)

Epithelial cells that lines body cavities and surfaces

Cell cycle control system

1.) A system that triggers the essential processes of the cell cycle.

2.) It ensures that the events of DNA replication, mitosis, and cytokinesis happens in order and that each process is complete before the next one begins

Molecular breaks

Checkpoints, used by the cell cycle control system, that allows them to pause the cycle at specific transition points if the criteria for the checkpoint is not met

3 different checkpoints

1.) At G1 —> Checks if the cell is in a favourable environment to divide

2.) End of G2 —> Checks if there is any damage to the DNA and if they’re fully replicated

3.) During M-phase —> Checks that the chromosomes are attached to the mitotic spindle

Yoshio Matsui experiment

They injected one egg with cytoplasm that came from a cell in M-phase and injected another with cytoplasm from a cell in interphase

Yoshio Matsui experiment observations

The cell injected with M-phase cytoplasm drove the cell to go into M-phase, while the cell injected with interphase cytoplasm did not.

Yoshio Matsui experiment conclusions

1.) There is something present in the M-phase cell that is not found in an interphase cell that causes the cell to enter M-phase.

2.) They later found that this component was MPF

MPF

1.) Maturation promoting factor

2.) Aka the cyclin-cdk complex made up of M-cyclin and cdk

Cyclin

1.) A protein with no enzymatic activity.

2.) Their role is to bind to the cell-cycle kinases, cdk, to make them enzymatically active.

3.) Their levels rise and fall in a cyclic fashion throughout the cell cycle

Kinase vs phosphatases

1.) Kinases puts on phosphates and phosphatases takes of phosphates, both of which can modify the activity of the protein they’re acting on

2.) This mechanism of phosphorylation and dephosphorylation is a common way of regulating protein activity

CDK

1.) Cyclin dependent kinase

2.) It is what the cell cycle control system relies on for regulation

3.) It is inactive by itself and needs to interact/bind to cyclin to become activated

Different cyclin-cdk complexes

There are different cyclins, each with their own corresponding cdk’s. These different complexes trigger distinct events in the cell cycle.

Different cyclins

1.) M cyclin

2.) S cyclin and G1/S cyclin

3.) G1 cyclin

M cyclin

It triggers entry into the M-phase from G2 by forming the M-cdk complex

S cyclin and G1/S cyclin

G1/S cyclin reassures the cell to go into S phase and S cyclin actually launches the cell into S phase, by forming S-cdk and G1/S-cdk

G1 cyclin

It tells the cell it is ready for replication by forming G1-cdks, which drives the cell through G1, towards the S phase

Cyclin concentrations

1.) G1/S cyclin increases at the beginning of G1 phase and then goes down at the beginning of S-phase

2.) S cyclin increases at the end of G1 phase and remains constant until it falls during the middle of M-phase

3.) M cyclin gradually increases at the start of G2 phase and then abruptly falls off at the end of M-phase

Cyclin concentration pattern

It gradually increases and then abruptly falls

Gradual increase of cyclin

It gradually increases as the cyclin genes are transcribed and then the cyclin proteins are synthesized.

Rapid fall of cyclin

1.) They are tagged by a ubiquitin chain, via APC/C for destruction.

2.) And as soon as they’re tagged, they are degraded, causing the abrupt fall of their concentration

APC/C

It ubiquitinates the cyclin, signalling the cell that it has to be taken to the proteasome for degradation

Ubiquitin

It tags proteins, acting as a signal that the protein has to be taken to the proteasome for degradation.

Ubiquitin during the cell cycle

It is mostly found in the middle of the M-phase

Rapid fall of cyclin AND cdk

Once cyclin is rapidly degraded, the cdk is no longer active, which is why they both abruptly call off at the same time.

Cyclin cdk activity

The activity of the cyclin-cdk activity abruptly turns on, unlike the gradual increase of the cyclin concentration

How the cyclin-cdk complex is made, turned off, and then turned on.

1.) Cyclin binds to the cdk but its activity is inactivated by the inhibitory kinase, Wee1, which phosphorylates cdk.

2.) The complexes activity is activated when the activating phosphatase, Cdc25, dephosphorylated the cdk

What do cyclin-cdks actually do

1.) They catalyze the phosphorylation and activation of hundreds of different proteins, especially those needed for mitosis

2.) It also shuts off the phosphatase protein that opposes phosphorylating activity

G1 to S transition

When the environment is not favourable for the cell to go through cell division, cdk inhibitors block entry into the cell cycle, specifically S phase, by preventing G1 cyclin from binding to cdk.

G2 to M transition

If the cell finds that the DNA has been damaged or DNA replication is incomplete, entry into M-phase is blocked by inhibiting phosphatase Cdc25, which keeps M-cdk inactive since Cdc25 is what activates it via dephosphorylation.

Delaying the end of mitosis

If a cell senses that the chromosomes are not properly attached to the mitotic spindle, the activation of APC/C is inhibited. Meaning that it can’t degrade M-cyclin, which delays the completion of mitosis.

DNA damage checkpoint in G1 (steps 1-2)

1.) DNA damage in G1 causes an increase in concentration and activity of protein p53.

2.) p53 then goes to the nucleus and binds to DNA, which influences the transcription of certain genes, specifically p21.

DNA damage checkpoint in G1 (steps 3-4)

3.) The gene encoding protein p21 (a cdk inhibitor) is activated, which is then transcribed and translated into the actual protein

4.) p21 then binds to the G1/S-cdk and S-cdk complexes, thereby preventing them from driving the cell into S-phase

What happens if p53 is defective

1.) If p52 is defective, p21 cannot be made, preventing the cell from having enough time to fix the damaged DNA before the next phase is initiated.

2.) The damaged DNA is eventually passed onto progeny, which can be detrimental, as it may cause cancer.