Lecture 18 - What are recessive and dominant mutations? Flashcards
Mutations can occur in any cell at any time…
Germline mutation = if a mutation occurs in a cell that foes on to make gametes, the mutation can be passed on to the next generation
Somatic mutation = occur in other cells and cannot be passed on - can result in cancer …Somatic mutations are always happening through mistakes in DNA replication or mutagens affecting the DNA such as UV light and we have lots of mechanisms in our cells to correct these mutations and repair our DNA, when this goes wrong, this can result in cancer.
What is cancer?
Cancer is a collection of related diseases and can start almost anywhere in the body.
Cancer cells are cells within a tissue that no longer respond to many of the signals that control cellular growth and death.
Over time, these cells become increasingly resistant to the normal controls in a cell that maintain normal tissue — and as a result, they divide more rapidly. - uncontrolled cell growth and cell division
Despite multiple abnormalities, cancer cells evade programmed cell death.
In the late stages of cancer, cells break through normal tissue boundaries and metastasize (spread) to new sites in the body.
Multiple mutations underlie the development of cancer
Cancer is the result of an accumulation of mutations. Most mutations associated with DNA replication. e.g. error of DNA polymerase causing wrong nucleotides to be incorporated or damage to the DNA that the cell hasn’t been able to repair.
The more times a cell divides, the more likely it to gain a mutation - this is why the incidence of cancer greatly increases with age. Because older people have undergone more cell divisions and therefore longer to accumulate change
Hundreds of genes encode proteins that normally regulate cell growth and division Mutations that alter these genes in somatic cells can lead to cancer Mutations may be spontaneous (occur by chance) or the result of exposure to a mutagen (also called carcinogen)
Cell division normally
Cell division is really well controlled at a molecular level so that new cells are forming all the time and so old cells are dying. Balance between cell proliferation and cell apoptosis.
Stem cells can divide and replenish the cells, their daughter cells then over a number of generations differentiate and become a skin cell for example.
Cell division and differentiation….usually cells have a defined number of cell divisions they undergo before they reach their differentiated state and then have a limited lifetime before they die.
What causes cancer?
The majority is due to ‘bad luck’ i.e. random mutations arising during DNA replication in normal, noncancerous stem cells. Inly a third of the variation in cancer risk among tissues is attributable to environmental factors and inherited predispositions.
Two types of genes cause cancer when mutated
Tumour supressor genes
Oncogenes
Tumour suppressor genes
Brake pedal
Encode proteins that normally prevent uncontrolled cell growth e.g.;
-proteins that inhibit cell division
-Prevent other mutations (DNA repair
enzymes)
Lack of these genes can stimulate cell growth - i.e. recessive mutations promote cancer
A gene whose protein product inhibits cell division, thereby preventing the uncontrolled cell growth that contributes to cancer.
If you have a mutation in one copy then you still have another copy that is going to prevent cell division but if you get two mutated copy then it is going to cause problems
oncogenes
Accelerator
Encode proteins that promote cell growth e.g.
• Proteins that stimulate cell division
Cancer mutations increase the activity of these genes
Dominant mutations promote cancer
genes that cause cancer by blocking the normal controls on cell reproduction
Only need to mutate one copy in order to increase activity in these genes
Inactivation of E2F transcription factor
Tumour supressor gene mutation …
This cell is prevented from undergoing cell division due to inactivation of E2F transcription factor.
Signal for cell division results in E2F transcription factor going to the nucleus. Cell division genes can then be expressed.
Loss of function mutation in RB gene causes activation of the E2F transcription factor
Loss of function mutation in p16 gene causes activation of the E2F transcription factor
Both must occur to have the adverse effect.
Kinase - some proteins are activated by phosphorylation (adding a phosphate) and here there is a kinase that is involved in suppressing cell division and there is another protein that is associated with the kinase to keep it in check and to ensure that it is active
E2F - held in the cytoplasm by binding to another protein called an RB which inhibits the effect of the transcription factor. Binds to DNA promoter region and turns on the transcription of genes and if you are going to undergo cell division then you have to activate a number of genes that are involved in this and the E2F transcription factors need to promote turning on the genes involved in DNA replication and cell division
Release of the inhibitor on the kinase, now kinase phosphorylates RB which causes a change in its conformation so it is no longer holding the transcription factor and this transcription factor is released and can move into the nucleus and then bind with the DNA of the genes that have the sequence that this protein recognises which causes transcription which kicks off cell division
Both must be mutated to have this effect. Inactivated it by having a mutation in the RB gene which means that it is no longer present in the cell so the transcription factor is no longer held in the cytoplasm and can freely move to the nucleus and bind. THis alone doesn’t cause uncontrolled cell division but it is a step towards it.
Common mutation in RB is linked to a range of cancers
How does oncogene result in an increase in gene activity ?
Proto-oncogene (a normal gene that when mutated can promote uncontrolled cell growth)
Mutations in the region controlling the amount of transcription, increases transcription as it now has an altered control region, normal growth stimulating protein in excess, results in increased cell growth.
Some transcription factors inhibit transcription so if you have a mutation in the binding sites for one of these then you would get a higher expression of that gene, so if you had more copies of mRNA you would have more protein being produced and an excess of protein that can stimulate cell division and growth when it shouldn’t.
Mutations in the protein coding region, increases protein activity, a protein is produced that is always active or is not degraded, results in increased cell growth
Can be always active….there are specific parts on a protein that are affected by phosphorylation and this phosphate group will activate or inactivate it. So if there is protein that is normally inactivated because it has a phosphate group added to it and if a particular part is mutated and can’t be phosphorylated then it can’t be inactivated by phosphorylation and will be in the active form all the time.
Not degraded…..Mutations in the areas that are usually recognised for the protein to be degraded so the enzyme can’t degrade and protein lasts longer than it should and causes cell division and growth when it shouldn’t
Oncogenes, increase in gene activity and chromosomal changes
Gene duplications - more copies of a gene leads to more protein being produced leads to activation and increased cell growth
Translocation - bits of chromosome can break off and move position which leads to increased production of a protein
Chronic myeloid leukemia - example of how oncogene and tumour suppressor mutations lead to cancer
Common mutation in this cancer is a translocation on the oncogene to produce BCR-ABL oncogene
Mutatiions in both copies of RB tumour suppressor genes
These both result in uncontrolled cell division
Common mutation = translocation between chromosome 9 and 22
- get ABL gene moving from 9 to 22
- BCR and ABL combine to give ‘gene fusion’
• Normally, ABL needs a cellular signal to activate it so it can promote cell division
• The BCR-ABL fusion protein is always active (no signal needed) —> oncogene
Having the tyrosine kinase always active will not lead to cancer if we have the tumour suppressor genes (i.e. RB)
• However, if we have the translocation and mutations in both copies of a tumor suppressor gene this will lead to uncontrolled growth —> can lead to cancer
Genetic predisposition
Inherited mutations increase chance of cancer
For example if you have an inherited (germline) mutation a tumour suppressor gene you now only need a mutation in the second copt rather than two mutations occurring at the same time in both copies.
Cancer treatments
Surgery - remove cancer cells
Radiation therapy - targeted radiation treatment to kill cancer cells
Chemotherapy - uses drugs that target dividing cells as cancer cells grow and divide rapidly - ut also affects normal cells
Mercaptopurine - DNA base analog that inhibits with enzymes that make dATP and dGTP nucleotides - analog of DNA nucleotides (not ones but look like them) and this drug targets enzymes that attack the precursors dRAP and dGTP needed for DNA replication. Bind to enzymes that make these and therefore body won’t have enough of these in them and therefore can’t replicate their DNA and therefore divide
Targeted therapy - drugs that target changes in cancer cell that allow them to grow and divide
