Cell sTRESS Flashcards
threats to the cell
Damage to proteins, lipids, nucleic acids chemical or physical insults
Nutrient deprivation
loss of metabolic energy supply and/or building blocks for macromolecules
Toxins (various actions) (Infections) may cause nutrient deprivation or other chemical changes (bacteria), or Invade cells (viruses), or produce biological toxins (bacteria)
DNA damage has unique consequences /Rna
Single copy of encoded information
Mutation permanent, may be lethal to the cell, or to the organism
Lasting damage from a single chemical change
Damage must be repaired, or else!
RNA
Multiple copies in cell
Damaged components may malfunction
Or they may interfere with normal function of remaining intact molecules
Damage more diffuse
Need to replace damaged components with new ones
What type of DNA damage is repaired by BER?
BER is used by the cell to correct damaged DNA bases or single-strand DNA breaks. These lesions often result from spontaneous DNA damage (DNA deamination or hydroxylation of bases) or by exposure to environmental alkylating agents.
What does the Loss or change of DNA bases occur by ?
Loss or change of DNA bases by spontaneous chemical reactions
Thymine
Thymine dimers induced by UV light
5-methyluracil, thymine (T) is a pyrimidine nucleobase, which pairs with adenine (A), a purine nucleobase. They are joined together as a base pair by two hydrogen bonds, which stabilize the nucleic acid structures in DNA.
What do Enzymes do ?
Enzymes recognise chemically altered single DNA bases and replace them
Repaired by Excision of a segment of DNA
More extensive damage (e.g., UV-induced dimers) get repaired by excision of a DNA segment
Why are Double Strands are harder to break ?and important to repair ?
No template strand available to identify correct sequence
May disrupt DNA replication
May disrupt proteins even if a strand breaks in an intron
Two strategies: Non-homologous end joining Homologous recombination
During DNA replication, the newly made strand guides repair of a strand break by “homologous recombination”
Homologous Recombination
What occurs during DNA replication
During DNA replication, the newly made strand guides repair of a strand break by “homologous recombination
What occurs during Mitosis ?
During mitosis, the sister chromatid may provide information for accurate repair by homologous recombination
DNA damage is sensed before, during, and after DNA synthesis
DNA damage detected here G2/M point
Starting Point
Cells audit themselves for DNA damage
A cell 4 hours after ionising radiation. Red/green pairs show multiprotein complexes assembled at sites of DNA damage.
Cellular outcomes of DNA damage
In response to DNA damage cells might:
- Repair the DNA
- Stop in cell cycle to repair DNA
- Go in permament cell cycle arrest (senescence) -
Activate apoptosis
What do P53 activate ?
P53 activates DNA damage……
via activation of expression of p21 and XPC
P53 can cause DNA repair - via transcriptional induction of p21. P21 binds PCNA (proliferating cell nuclear antigen), a protein that has a role in DNA synthesis and repair. - Via transcriptional activation of XPC, a protein involved in nucleotide excision repair
Summary: DNA damage
Examples
Loss of bases (e.g., depurination)
Change of single bases (e.g., deamination) Dimerisation(UV-induced)
Strand breaks
Replication errors by DNA polymerase
Normal rate of damage too high for survival
Repair mechanisms required
Where does Protein Folding occur ?
Protein folding begins during translation at the ribosome
Protein folding is disrupted at elevated temperature
Is proteins Folded ?
In cells, protein folding is assisted and monitored
Misfolded and aggregated proteins may accumulate in cells subjected to heat stress (for example
) • Deprives cell of the affected protein functions, and aggregates may be toxic
“Molecular chaperones”
perform the same function for proteins.
prevent both newly synthesised polypeptide chains and assembled subunits from aggregating into nonfunctional structures.
What do the HEAT SHock Protein ?
“Heat shock protein”-70 binds hydrophobic regions of unfolded proteins to prevent aggregation
What occurs during the HP60 LATER ?
Later during folding, Hsp60 provides a protected environment for protein folding
What does the Proteasome ?
The “proteasome” degrades misfolded and ubiquitin-tagged proteins
Complex Sugars are attached to what ?
In the ER, complex sugars are attached to growing polypeptides
Er Glycoproteins ?
ER glycoproteins are monitored for folding by the combined action of a glucosyl transferase and calnexin
Where Aare the Badly ones sent to ?
Badly misfolded ER proteins are sent back to the cytosol and degraded by the proteasome
Where does the increased Temperature do ?
Increased temperature raises the level of unfolded proteins, directing the production of more chaperones
Heat shock Response is what ?
The heat shock response is an example of negative feedback regulation, which allows cells to adapt to stress
protein folding stress
Protein misfolding occurs all the time
Controlled by chaperones (Hsp70, Hsp60) and the proteasome
Worsened by elevated temperature and other factors, such as: High level of secretory protein production Viral infection (making viral coat proteins)
When occupied by unfolded proteins,
Hsps are released from stress-responsive transcription factors
The transcription factors go to the nucleus and direct the production of more heat shock proteins
This increases capacity to cope with misfolding
