Cell metabolism-resultant production of free radicals, UV light, Ionizing radiation, chemical exposure & replication errors
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Solutions to DNA damage
Cell cycle checkpoint activation, transcriptional programme activation, DNA repair of apoptosis
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What happens when a single strand breaks
DNA replication causes it to become a double-stranded break. This causes aneuploidy, chromosomal rearrangements, mutations and cancer.
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What is aneuploidy
The wrong number of chromosomes
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which proteins recognise broken DNA strands?
Kinases ATM and ATR
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What is a kinase?
Enzymes that transfer a phosphate group onto another molecule
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What is the use of kinases?
Many proteins are regulated by phosphorylation - can be activated or inactivated by the addition of phosphates
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What happens when DNA damage is detected by ATM/ATR
They phosphorylate/activate Chk1 and CHK2 (checkpoint) protein kinases. CHK1/2 then phosphorylate the P53 protein
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what is the P53 protein?
one of the most important tumour suppressors - regulate & prevent overgrowth of cells
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What % of cancers have a mutation in the P53 protein?
around 50%
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What does P53 do?
Transcriptional activator - binds to DNA and directly switches on genes nearby. Induces genes required for DNA repair, cell cycle arrest or apoptosis
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How does the cell decide between cell cycle arrest and apoptosis?
4 acitvates P53s join together to form a tetramer which binds to DNA. tetramer can interact tightly (high cooperativity) or weakly (low). low cooperativity = growth arrest high cooperativity = apoptosis
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What is the purpose of the cell cycle?
Prevent uncontrolloed growth,
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Where are there checkpoints in the cell cycle?
end og G1, G2 and metaphase - check conditions arre correct before continuing
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What is the cell cycle controlled by?
Cyclic proteins - expressed in cell according to phase
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What are the cyclins required for?
Activity of kinases -cdks(cyclin dependent). cyclin associates with specific cdks to form functional pairs
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/initiation of S phase
Require signal from cell environment. controlled by E2F proteins(required for gene transcription)
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What happens at begginign of G1 phase, stopping movement into S phase?
E2F proteins bind to Rbp (Retinoblastoma) protein which represses S genes, kepping the cell in G1
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What happens to initiate the cell cycle?
cyclin D is expressed in repsponse to environmental signals telling the cell to divide. this activates Cdk4 which then the Cdk4/CyclinD complex them phosphorylates Rb protein. Rb no longer interacts with E2F so dissociates
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cont
when Ef2 dissociates, transcriptional regression is lifted and EF2 transcribes the genes which drives the cell into the S phase. Cylin D in unneeded so degrades. Cyclin E activates Cdk2 which activates proteins needed for progression to S phase
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What happens when the cell detects damage?
It activates p53
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What effect does p53 have?
transcriptional activator - induces expression of p21 gene (a CKI (Cdk inhibitor)
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Whats does p21 do?
Binds to the cyclin/Cdk complex and prevents it from phosphorylation pRb. prevents expression in S phase and causes cell to arrest in g1.
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What happens if the DNA damage is repaired?
the inhibition can be relieved and the cell cyclie resumed
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What is apoptosis?
Programmed cell death - mechanism for the controlled removal of unwanted or damaged cells
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How is apoptosis induced?
Driven by activation of proteases (protein degrading enzymes) - caspases
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How is it repressed in healthy cells?
BH123 proteins that when aggregated form a complex and release cytochrome C are prevented by aggravating by Bc12 proteins
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What happens in response to DNA damage and p53 activation?
p53 activation is an apoptotic signal causing initiation of apoptosis
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What effect does chytochrome C have?
when it's released from the mitochondria causes assembly of the apoptosome. CytoC binds to apoptotic protease activating factor which form a heptameric complex called the apoptosome. This recruits ad activates procaspase 9 for active procaspase-9
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Other cards in this set
Card 2
Front
Solutions to DNA damage
Back
Cell cycle checkpoint activation, transcriptional programme activation, DNA repair of apoptosis
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