Cell cycle: regulation

Cell cycle: regulation

Cells do not progress through their life cycle for no particular reason. Each
phase is coordinated by internal genetic signals and external cues.
- Coordination of growth and development between 30 trillion cells is critical.

Genes that control the lifecycle of each cell act

as guidelines or laws for how each cell should
behave.

Cells contain mechanisms, such as regulatory genes,

that encourage or inhibit cell growth and division.
 Cell cycle: regulation

Genetic control of the cell cycle:

• Certain classes of genes, known as proto-oncogenes or growth factors,
produce proteins that encourage the cell to progress through the cell cycle if
conditions are favorable (gas pedal for cell cycle).

• In contrast, cell cycle control genes (growth suppressors) produce proteins that
prevent the cell from progressing through the cell cycle if the cell is ill
prepared, damaged, or external cues are unfavorable (brakes for cell cycle).

Cell cycle

Control genes Growth factors

Cells contain regulatory genes, that encourage or inhibit cell growth and
division based on feedback from other cells and the environment.
 Cell cycle: regulation

Cells are pushed through the cell cycle by growth factors but are checked at key
cell cycle checkpoints by cell cycle control proteins:

Before moving to S phase… Before moving to mitosis… Before moving to anaphase…

G1 checkpoint G2 checkpoint Spindle (M) checkpoint
• Has DNA been damaged? • Has DNA been damaged? • Are all chromosomes present
• Is the cell developed enough? and attached to spindle fibers
• Have all the chromosomes during metaphase?
• Does the cell have enough been duplicated?
nutrients stored to replicate
its genome?
G2 checkpoint Spindle (M)
checkpoint

Cell Cell Cell

Cycle Cycle Cycle

G1 checkpoint
 Cell cycle: regulation

Much of the cell cycle checkpoints revolve around DNA integrity.

DNA repair genes – encode proteins that correct/repair many DNA mutations
- Many mutations that arise throughout the life of a cell can be repaired by the
proteins of these genes

A T
C ? Must have been a “G”

C G
T A
- Complementary base-pairing
A T
allows DNA repair proteins to
G C
correct damaged bases
A T
A “C” will complement ? G
this “G”
T A
T A
 Cell cycle: regulation

If a cell cannot meet the requirements to pass a cell cycle checkpoint another
type of cell cycle regulation gene will activate and produce proteins that will
cause the cell to undergo apoptosis. Apoptosis is a kind of cellular self-destruct
mechanism where by a cell causes its own death.
- A major purpose of apoptosis is to prevent damaged/defective cells from
producing more damaged/defective cells.

Apoptosis

Cell rounds up, losing DNA condenses, and

contact with neighbor nucleus fragments. Plasma membrane Cell dissolves into
cells, and nucleus blisters. fragments.
collapses.

- Failure of apoptotic genes to function, plus continued accumulation of DNA

damage, can lead to cancer
 Mutation

Gene mutation is a process by which the sequence of base pairs in a DNA

molecule are altered.
- Mostly occur randomly within the genome of a cell over time
- Most mutations do not lead to cancer but certain specific mutations can.

Mutation effect on a protein can vary:

- No effect
- Reduced functionality
- Loss of function – protein from gene no longer fulfills
its original functional purpose
- Gain of function – protein is altered in such a way
that it has a brand new function in the cell/body
 Mutation

Endogenous mutations – mutations originating from inside the cell itself

Endogenous mutations may result from:

- Errors in DNA recombination

- Some exchanged DNA might be lost or altered
during the process

- Errors during DNA replication

Example: during DNA replication the wrong
nucleotide might be inserted into the copied
DNA strand.
- When cells divide they must make a copy of their
genome, sometimes the DNA may be copied
incorrectly
- Chemical degradation
- DNA nucleotides can degrade randomly as
a result of internal cell conditions
 Mutation

Exogenous mutations – mutations created by a factor from the external

environment

Mutagen – a physical or chemical agent that alters DNA

- increases the frequency of mutations above the
endogenous background level

Include: radiation (UV, X-Ray), harmful chemicals, and viruses

UV light can degrade DNA structure
and thereby cause mutations.
 Point mutations

A mutation that results in the change of a single DNA nucleotide is known as

a point mutation.
- If it occurs in the protein coding sequence of a gene, one codon (or more) will be
altered.
- May lead to change in the amino acid(s) during translation

Types:
• Silent mutation
• Missense mutation
a. conservative
b. non-conservative
• Nonsense mutation
• Frameshift mutations
a. insertion
b. deletion
 Point mutations

Silent mutation – a change in a DNA nucleotide that results in the same amino
acid being incorporated into the protein
- No change in protein (mutation would go unnoticed in the cell)
- Degeneracy of genetic code allows for this

Change the lettering, but the “meaning”

remains the same.
 Mutation

How will the protein be affected by a silent mutation?

Primary Tertiary
Ala Ala
Original: Ala
Ser Ala Lys Ala
Ser Ala
Ser
Ser
Lys
Ala Lys Lys Ala

Ala Ala

Ala Ser Ser

Silent mutant: Ser Ala Lys Ala
Ser Ala
Lys Ala Lys Lys Ala
 Point mutations

Missense mutation – a change in a DNA nucleotide that results in a different

amino acid being incorporated
a. conservative – changes amino acid to another with the same properties
- If the property of the new aa is similar to the original, the effect on the protein
will likely be minimalized (reduced functionality).

Nonpolar Polar Basic

Acidic

Lysine and Arginine both have

basic side groups.
 Mutation

How will the protein be affected by a conservative missense

mutation?
Primary Tertiary

Ala Ala
Original: Ala
Ser Ala Lys Ala
Ser Ala
Ser
Ser
Lys
Ala Lys Lys Ala

Ala Ala
Ala
Conservative Ser Ala Arg Ala
Ser Ala Ser Ser
Lys
missense mutant: Ala
Arg
Lys Ala
 Point mutations

Missense mutation – a change in a single DNA nucleotide that results in a

different amino acid being incorporated
b. non-conservative – changes amino acid to one with a different property
- Most likely will lead to reduced functionality or loss of function.

Nonpolar Polar Basic

Acidic

Lysine and threonine exhibit

different side-group
properties.
 Mutation

How will the protein be affected by a non-conservative

missense mutation?
Primary Tertiary

Ala Ala
Original: Ala
Ser Ala Lys Ala
Ser Ala
Ser Ser
Lys
Ala Lys Lys Ala

Ala

Ser Ala
Ala
Non-conservative Ser Ala Thr Ala
Ser Ala
Ala Ser
Lys
missense: Thr
Lys Ala
 Point mutations

Nonsense mutation – a change in a single DNA nucleotide that results in a

STOP codon
- Prematurely ends the growing amino acid chain
- Similar to putting a period (.) in the middle of a sentence.
- Typically renders the protein nonfunctional (loss of function)
Stop codons do not code for
amino acids.
 Mutation

How will the protein be affected by a nonsense mutation?

Primary Tertiary

Ala Ala
Original: Ala
Ser Ala Lys Ala
Ser Ala
Ser
Ser
Lys
Ala Lys Lys Ala

Ala

Ala Ser
Nonsense mutation: Ser Ala
Ala
 Point mutations

Frameshift mutation – caused by the insertion or deletion of a nucleotide in a

DNA sequence
- Almost always results in a loss of function for the protein
- Shifts the codon reading frame
 Point mutations

Frameshift mutations

Remember: codons are read every three RNA nucleotides beginning with the START
codon.
Analogy:

Codon Original sentence: THE CAT ATE THE RAT

1 2 3 a. if letter C is deleted, reading frame shifts:

A A A After deletion: THE ATA TET HER AT
U U U
C C C b. if a letter C is inserted, reading frame shifts:
G G G
After insertion: THE CCA TAT ETH ERA T
 Mutation

How will the protein be affected by a frameshift mutation?

Primary Tertiary

Ala Ala
Original: Ala
Ser Ala Lys Ala
Ser Ala
Ser
Ser
Lys
Ala Lys Lys Ala

Ile Lys
Phe
Iso
Ala
Met
Ala Val Val Iso Ser
Frameshift mutation: Ser Ala Met
Ile Phe Val
Lys Val
Ala
 Cancer

Cancer is a group of diseases involving abnormal cell growth due to mutations in

genes that control the cell cycle and DNA repair.

- Each occurrence of cancer is unique

- Different cells receive different
mutations over a lifetime

- Mutations arise due to endogenous

or exogenous mutations
- Exogenous mutations increase the risk of
mutations beyond background
endogenous mutations.

A Biography of Cancer – Siddhartha Mukherjee

 Cancer

Effects of mutation:
• If DNA repair genes are themselves mutated, the DNA repair
ability of the cell plummets, furthering mutational damage
- i.e. the proteins responsible for fixing damage are themselves damaged

• If proto-oncogenes mutate, they become oncogenes which

constantly stimulate cell division, no matter the conditions
Proto-oncogenes = good (functional), oncogenes = bad (hyperactive)

• If growth suppressor genes mutate, they cannot halt cell

division and therefore cells continually divide without regard
for optimal internal cell conditions
 Cancer

Researchers believe that cancer results from the accumulation of mutations

across multiple cell regulation genes in somatic cell lines. This is known as the
multiple-hit hypothesis.
- Mutations must accumulate in multiple gene classes (proto-onco, growth
suppressors, DNA repair) in a single cell for cancer to occur.
Analogy: In some cars there are multiple ”brakes”, one for each wheel. Therefore
it would take more than one to be cut before a car fails to stop.

Mutation in one copy of a Mutation in both copies of a

Normal cell
growth suppressor gene. growth suppressor gene.
 Cancer

Origin of cancer
1. Cells are continuously replaced
in the human body (mitosis).
- Billions an hour
- Implies constant DNA replication
and division

2. Cells are constantly exposed to

exogenous mutagens in the
environment as well as endogenous
mutations.

3. Each daughter cell inherits the

mutations of the previous generation
(old mutations).
 Cancer

Mutations are passed on cell division

after cell division.

A cell, with multiple non-functional cell regulation genes,

may undergo rapid cell growth and division creating a
mass of cells known as a neoplasm (tumor).
Mutations inactivate DNA repair
- The cells resulting from division of this original mutant
genes.
cell contain the same mutations of the original cell and
Mutation of proto-oncogene creates
even new mutations as the cell checkpoints no longer
an oncogene
exist.
Mutation inactivates growth
- Cells of the neoplasm do not cooperate with the rest
suppressor gene.
of the body cells, they now compete with them.

Neoplasm