Block 2. Lecture 11. Mutations and cancer Flashcards
Mutations in what part of RNA are more likely to impact the final protein?
in the coding regions(exons)
as opposed to introns( can also have an impact but not as often)
Effect of DNA sequence changes
Mutations CAN affect the structure and function of a protein.
Why do mutations in the DNA not always have an impact on the protein?
mutation occurred in the non-coding regions
2 main types of DNA sequence changes effects
germ line-passed on to future progeny
local/somatic- during cell division, local effects(sun)
Large scale DNA alterations
chromosomal rearrangements ( bad swapping)
Small scale DNA alterations
one or few nucleotides altered
Types of small scale mutations
Substitutions – where one base is replaced by another - can have minimal or major effect
Insertions/Deletions –can have major effect if within coding sequence - can cause a frameshift
Substitutions can be:
silent
missense
nonsense
Insertions or Deletions (indels):
cause frameshift if 1 or 2 nucleotides
can maintain frame if 3 nucleotides
Silent mutation
1 nucleotide pair is substituted in place of another.( in DNA)
The spelling of the DNA and subsequent RNA has changed, the amino acid coded for is THE SAME!! No effect on the protein.
Missense mutation
1 nucleotide pair substituted in place of another( in the DNA)
codon changes and AA produced is different
the impact depends on the role of the amino acid in the protein and where in the protein if has occurred
nonsense mutation
1 nucleotide pair substitution causes a change from the original codon to the stop codon. The translation of the protein is stopped. Creates a truncated protein.
the effect depends on where in the protein it occurred ( at the start or towards the end)
frameshift mutation via insertion
extra nucleotide inserted. Causes all the codons from that point on to change.
Can again create a stop codon, stopping the translation of protein. Causes immediate nonsense
frameshift mutation via deletion
a nucleotide is missing(taken out)
changes all the codons from that point on.
Frameshift. The entire protein from that point has changed.
Can have a catastrophic effect!!!
effect depends on the position in protein to SOME degree
3-nucleotide pair mutation
3 -nucleotide pair deletion
1 codon is lost, but downstream residues are intact, the frame is maintained.
the effect depends on the role of AA in the protein.
Huntington’s disease
due to triplet repeat expansion.
Triplet repeat /polyglutamine diseases. Codons coding for glutamine are inserted
Normal Huntington’s gene- glutamine repeat length 15-19
Mutation- over 40!!
sickle cell anemia
Example of missense substitution mutation.
Hemoglobin within RBC is made up of 4 different proteins. They form quaternary structures( alpha-globin and beta-globin come together to form hemoglobin)
In sickle cell disease, there is a mutation in beta-globin DNA, where nucleotide T is substituted with A. This changes the mRNA codon from GAG to GUG. Instead of glutamic acid Valine AA is formed. Valine is a hydrophobic AA as compared to hydrophilic Glu.
The shape of RBC change and it is harder for them to pass through narrow capillaries, which can clog the capillaries.
what is MPF
Maturation promoting factor (MPF) is the cyclin-Cdk complex, a cell cycle checkpoint that regulates the passage of a cell from the G2 growth phase to the M phase. It is also known as the G2 checkpoint and ensures that DNA replication during the S phase did not produce any mistakes
Cyclin: a protein that fluctuates throughout the cell cycle
Cyclin dependant kinase (Cdk): a kinase that is activated when attached to a cyclin
how MPF works
it phosphorylates many proteins to allow mitosis to commence
In cancer, what are common genes that get affected by DNA changes?
Proto-oncogenes - genes that normally stimulate cell proliferation( overactivation occurs)
Tumor suppressor genes - genes that normally keep proliferation in check( deactivation )
alterations in these can result in uncontrolled cell growth
What happens from mutation of proto-oncogene
in cell signaling, RAS is a G-protein(coded for by proto-oncogene)
normally works when tyrosine kinase is being activated by a signal to cause cell division
when RAS is mutated it activates the phosphorylation cascade without the signal from the receptor. The cell divides without a signal and causes exaggerated cell growth
examples of proto-oncogene
RAS- a GTPase
Myc- a transcription factor
deactivated tumor suppressor gene
loss of breaks
when DNA damage happens in normal cells, an active form of p53 forms, and it orders the cell to produce inhibitory protein to prevent cell division
if p53 is mutated it is not expressed in the cell and the inhibitory protein is not produced. Cell with damaged DNA divides
deactivated tumor suppressor genes examples
TP53
BRCA1 &2
what needs to happen for cancer to develop
multiple DNA changes. Not just one
