Sources and consequences of genomic instability Flashcards
For each type of break, what is there?
Specific tool kit and within that tool kit there are some shared components.
Is DNA stable?
Very stable inside the cell.
Very unstable outside the cell.
Why is DNA unstable within the cell?
Reactive oxidative species and enzymes mean DNA becomes unstable.
~7 lesions cell minute.
When are DNA breaks good?
When in an programmed way.
Immunoglobulin diversity. Fight infections. Introducing breaks and reshuffling the viable region in antibody to produce/develop antibody for each infection.
Meiosis: generate diversity in population by introducing break, reshuffling DNA between parents.
Turn on and off gene expression.
Introduce a break, conformation of that circuit changes and closes on itself. Change can be expressed.
What are the consequences of un-repaired DNA damage?
Cell death (degenerative disease and autoinflammation and cell survival (cancer)
Breaks exceed certain threshold.
If you have lots of cell death due to unrepaired breaks.
Causing degeneration in organs. Most affected organ is the nervous system.
Autoinflammation.
What is another consequence of un-repaired DNA break?
Other consequence is that cells may decide to continue dividing (cell survival) in presence of DNA break. Induce mutations and then cause cancer.
Link between genetic instability and cancer
See enrichment of mutations in protein-coding genes involved in DNA damage response (DDR).
Mess up DNA repair = cancer.
How might disease of the nervous system arise?
Only born with certain number neurons, exposed to various stresses. Those neurons if they accumulate damage in DNA by time function will be compromised. Causing disease in nervous system.
People living linger is increasing, putting pressure on health system.
What threatens genomic integrity?
Impaction – generate lots of supercoiling, tangling which needs to be unwinded.
If they were to transcribe to RNA, replicate during cell devision and there is recombination.
Done by enzymes topisomerese – these enzymes unwind. Do this dangerously by introducing a break in one or two strands of double helix. Then allow swivelling of other strand around the transient nick.
Oxidative and protein-linked DNA breaks
Reactive oxygen species
DNA topoisomerase
By-products during demethylation of histones and DNA (formaldehyde).
What is the concept behind impaction threatening genomic integrity.
Concept – there are enzymes in the cell that are very important to relax super coiling, during process they can break. End up with bit of protein stuck on DNA termini.
How does gene transcription - Epigenetic re-programming at regulatory regions producs ROS (very new) - pose a threat to genomic integrity?
Histone demethylation and DNA demethylation.
During cell transcription activation you need to remove certain silencing marks, histones are methylated. Need to remove methyl group on histones to turn on genes.
As a by product of demethylation you can produce oxidative stress.
Same happens ensuring DNA methylation.
Methyl cytosine? Common epigenetic mark which prevents gene expression. To turn of gene expression you need to remove the methyl group from 5-methyl cytosine. This is done by methylases and as a by product is generates ROS.
What is the main concept behind turning on gene expression?
Understand concept of that during turning on gene expression you need to remove methyl groups from histone from DNA. During demethylation ROS are produce as a by product and go on and damage nearby DNA.
Does DNA replication pose a threat to genomic integrity? How? (add this)
Yes
Epigenetic re-programming in the non-coding genome produces ROS.
Those types of reprogramming during gene activation are most pronounced gene regulatory elements.
The bit that is very vulnerable to this type of damage is the regulatory region, not necessarily the protein coding region. The non-coding region, ie promotor and enhancers – these regions have the most methylation events.
