Lecture 11: CSF DNA Mutations and Cancer Flashcards
What are mutations?
A random change in DNA base sequence
How do mutations occur?
Germ line - passed on to future progeny
Local/somatic - during cell division, not whole body - local effects (formation of tumours)
What are the two types of DNA sequence alterations?
Large scale and small scale
What are the types of small scale mutations?
Substitution
Insertion/deletion (Indel)
What is substitution mutation?
When one base is replaced by another
What is insertion/deletion mutation?
An addition or deletion of a base -> can cause frameshift
What are the types of substitution mutations?
Silent
Missense
Nonsense
What is a silent substitution mutation?
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
What is a missense substitution mutation?
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
What is a nonsense substitution mutation?
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
What is a frameshift mutation?
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
What are the effects of a frameshift mutation?
Catastrophic -> the protein is completely altered from the point of frameshift
What is a 3 nucleotide-pair mutation?
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
What is sickle cell anaemia?
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.
What is cyclin?
A protein that forms the maturation promoting factor along with cyclin dependant kinase
What is cyclin dependant kinase?
A kinase that is activated when attached to cyclin
What is MPF?
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
When is cyclin produced?
During G2 phase
When is cyclin broken down?
During mitosis
How do checkpoints function?
They make use of stop and go molecules
What are stop molecules?
Proteins associated with checkpoints that keep proliferation in check
What are go molecules?
Proteins associated with checkpoints that stimulate cell proliferation
How is a tumour formed?
From uncontrolled cell division due to DNA mutations that cause the over-activation of protooncogenes or the deactivation of tumour suppressor genes
How do cancer-causing DNA mutations arise?
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
What are proto-oncogenes?
Genes that have the potential to stimulate cell proliferation - go molecule
What are tumour suppressor genes?
Genes that keep proliferation in check - stop molecule
How does proto-oncogenes cause tumours to form?
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
How do deactivation of tumour suppressor genes cause the formation of tumours?
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
Does cancer occur from a single mutation?
No, typically multiple DNA changes are required
e.g. over activation of multiple proto-oncogenes
deactivation of multiple tumour suppressor genes
