Lecture 11: CSF DNA Mutations and Cancer

Question 1

What are mutations?

Answer 1

A random change in DNA base sequence

Question 2

How do mutations occur?

Answer 2

Germ line - passed on to future progeny

Local/somatic - during cell division, not whole body - local effects (formation of tumours)

Question 3

What are the two types of DNA sequence alterations?

Answer 3

Large scale and small scale

Question 4

What are the types of small scale mutations?

Answer 4

Substitution

Insertion/deletion (Indel)

Question 5

What is substitution mutation?

Answer 5

When one base is replaced by another

Question 6

What is insertion/deletion mutation?

Answer 6

An addition or deletion of a base -> can cause frameshift

Question 7

What are the types of substitution mutations?

Answer 7

Silent
Missense
Nonsense

Question 8

What is a silent substitution mutation?

Answer 8

When a nucleotide-pair substitution in DNA sequence does not result in the change of the amino acid coded for

E.g. GGC becomes GGU both code for glycine

No effect on protein formed

Question 9

What is a missense substitution mutation?

Answer 9

A nucleotide-pair substitution in the DNA sequence that changes the amino acid of the protein

E.g. GGC becomes AGC codon hence Glycine becomes serine

A single amino acid changes hence the effect depends on the role of the residue

Question 10

What is a nonsense substitution mutation?

Answer 10

A nucleotide-pair substitution that results in change of a codon to a stop codon stopping the formation of the polypeptide protein chain.

E.g. AAG becomes UAG meaning lysine amino acid becomes a STOP

Formation of a truncated protein

Question 11

What is a frameshift mutation?

Answer 11

An addition or deletion of a nucleotide pair that results in the shift of nucleotide pairs and hence changes the codon of the amino acids from that point on

E.g. AGU CGA UCA
AUG UCG AUC A

hence results in either a STOP codon being formed and hence truncated protein formation or a totally different amino acid chain compared to the non-mutated DNA

Question 12

What are the effects of a frameshift mutation?

Answer 12

Catastrophic -> the protein is completely altered from the point of frameshift

Question 13

What is a 3 nucleotide-pair mutation?

Answer 13

Addition or deletion of a codon (triplet of nucleotide pairs)

No frameshift, but addition or deletion of an amino acid of the protein -> a single amino acid can be added or lost but the frame of the protein is maintained

Question 14

What is sickle cell anaemia?

Answer 14

An example of a missense substitution mutation in the DNA coding for part of the red blood cell in which a nucleotide pair substitution causes a change in the amino acid from glutamic acid to valine

Causes the formation of a sickle shaped red blood cell compared to the standard round disk shaped RBC.

Question 15

What is cyclin?

Answer 15

A protein that forms the maturation promoting factor along with cyclin dependant kinase

Question 16

What is cyclin dependant kinase?

Answer 16

A kinase that is activated when attached to cyclin

Question 17

What is MPF?

Answer 17

Maturation promoting factor is a complex formed when cyclin dependant kinase binds to cyclin causing the phosphorylation of many other proteins and hence allowing mitosis to occur -> functions at the G2 checkpoint

Question 18

When is cyclin produced?

Answer 18

During G2 phase

Question 19

When is cyclin broken down?

Answer 19

During mitosis

Question 20

How do checkpoints function?

Answer 20

They make use of stop and go molecules

Question 21

What are stop molecules?

Answer 21

Proteins associated with checkpoints that keep proliferation in check

Question 22

What are go molecules?

Answer 22

Proteins associated with checkpoints that stimulate cell proliferation

Question 23

How is a tumour formed?

Answer 23

From uncontrolled cell division due to DNA mutations that cause the over-activation of protooncogenes or the deactivation of tumour suppressor genes

Question 24

How do cancer-causing DNA mutations arise?

Answer 24

Genetic predisposition : occurs in all cells of the body due to inheritance of an issue or deficiency in a gene

Acquired: locally, in a single cell initially due to carcinogens such as UV damage, smoking, viruses, drugs and treatments

Question 25

What are proto-oncogenes?

Answer 25

Genes that have the potential to stimulate cell proliferation - go molecule

Question 26

What are tumour suppressor genes?

Answer 26

Genes that keep proliferation in check - stop molecule

Question 27

How does proto-oncogenes cause tumours to form?

Answer 27

Allow activation of G protein and phosphorylation of kinase molecules to form the transcription factor without the need of growth factors binding to a receptor

The uncontrolled formation of transcription factors will cause the overexpression of a protein stimulating cell cycle and hence increased cell division

Question 28

How do deactivation of tumour suppressor genes cause the formation of tumours?

Answer 28

Normally, when DNA is damaged, a tumours suppressor gene will activate a transcription factor which causes the formation of an inhibitory protein that prevents the cell cycle from occurring.

Deactivation of tumour suppressor genes means that the transcription is defective or non existent meaning the inhibitory protein cannot be produced and cell cycle cannot be prevented

Question 29

Does cancer occur from a single mutation?

Answer 29

No, typically multiple DNA changes are required

e.g. over activation of multiple proto-oncogenes
deactivation of multiple tumour suppressor genes