Eukaryotic genetic regulation Flashcards
(17 cards)
central dogma
DNA - PolII - > mRNA - ribosome-> protein
Transcriptional activation of oestrogen receptor (ER)
ER is a transcriptional factor and a nuclear receptor
oestrogen binds to ER (pushes HSP90) goes to the nucleus where it binds to CoA and RNA pol starts transcription
chromatin
fundamental - nucleosome
pack DNA - physical barrier to proteins and transcriptional machinery
modulate nucleosome: chemical modifications to N- of histone rich in lysine
HDACs gene expression
HAT (acetylation) - opens and facilitates transcription
HDACs (deacetylation) - closes chromatin - repression of genes
histones
H3, H2A, H4 and H2B
HFD: DNA wraps around this area
- flags represent sites of modification
H2AX
alarm for damage and classic marker of cancer
kinase ATM phosphorylates site damaged and DNA damage response comes
distribution of chromatin
heterochromatin (dense)- edge of nucleus - attached to LADs (lamin
euchromatin (open)- centre
never overlap
exception of central dogma
mRNA to DNA (reverse transcriptase) - viruses
transcriptome and diseases
problems with transcriptional memory (dysruption of transcriptional maintenance system)- low differentiation or anaplasia - malignancy
metastic - too much expression
EZH2
histone methyltransferase: 3 methyl onto lysine 27 in H3
signal to be switched off
repressive mark
Transcriptional activation via ER
oestrogen is lipid soluble so crosses membrane but only has effect in cells with endogenous ER
in absence of oestrogen, ER stays innactive connected to HSP90
only activates transcription when bound to oestrogen
hypoxic response
activation of hypoxia induced factor 1 (HIF1a)
hypoxia <1%
when there is normal levels of O2: Hf1a hydroxylated by PHD that is a signal for ubiquitination leading to degradation of the protein by pVHL
where there is lack of O2: this pathway is switched off and HIF1a goes into the nuclues and activated - VEGF gene expression
Vascular endothelial growth factor- new blood vessels (angiogenesis)
EPO - more red blood cells
pH regulation and glucose metabolism
DNA damage response
activation of p53 (guardian, cancer policeman, transcription factor) - stress
binds to DNA as a tetramer
activates transcription (mostly)
p53 and MDM2 co-regulation
- DNA damage - activation of ATM and Chk1 kinases (phosphorylation of H2A and p53) - nucleus and activates transcription or downstream genes
p21 (dependent kinase inhibitor) - stop growing (stop cycling CDK - G1 arrest)
GADD45/PCNA - proliferating cell nuclear antigen: stimulates DNA synthesis to repair damage
BAX - death (apoptosis)- if nothing works
MDM2 - ubiquitin ligase - p53 destroyed to prevent uncontrolled apoptosis
cancer
genetic disease caused by mutations
expression of oncogenes and loss of tumour supressors (p53)
p53 OFF - evading apoptosis - mutations in DNA binding domain because can´t activate P21, BAX - can´t stop tumour from growing (50% of all cancers)
overexpression of ER - self sufficiency in growth factors (70% breast cancer) - tamoxifen binds to ER and changes shape so that can´t bind to CoA (no expression) but trasncription factors are diff to drug (but is a nuclear receptor also)
loss of pVHCL constitutive HIF1 - switches gene on (increased angiogenesis and tumourgenesis) - 75% kidney cancers
other ways of inactivation of p53
DNA viruses (SP40)
nuclear exclusion (goes to cytoplasm)
activate MDM2 to switch off p53 (AKT and PTEN)
reactivation of p53
Lox-STOP-LOX (mice)
you can remove the STOP
Mutations of histone H3 and cancer
Instead of trimethylation of H3 in lysine 27 to switch off gene –> H3.3 mutant leads to dominant inhibition of EZH2 - global loss of H3K27me3
