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CONTROL OF EUKARYOTIC GENE EXPRESSION (premise of regulation (housekeeping…
CONTROL OF EUKARYOTIC GENE EXPRESSION
CONTROL AT CHROMATIN LEVEL
by controlling chromatin structure through
chromatin packaging
(ref. orgnisation of genome)
access of general transcription factors and RNA polymerase to DNA is dependent on
nucleosome
how tightly coiled it is
dependent on
Post transcriptional modification of histones
HISTONE DEACETYLATION
results in histones with acetyl groups (acetylated histones) losing acetyl group
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HISTONE ACETYLATION
at amino groups in lysine residue in N terminal end of histone molecules
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catalysed by histone acetylases
modification of residues in DNA
DNA METHYLATION
controls access of GTF to transcription factors
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found of transcriptionally silent regions of genome
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changes appearance and structure of DNA without changing sequence
occurs on recognition sites with cytosine (CpG rich)
because transcription factors require CpG rich sites to bind to DNA
leads to
premise of regulation
housekeeping genes
necessary for basic functional and structural purposes
on all the time
constitutive genes
not expressed all the time
differentiated cell type express different genes required for their specialised structure and function (not all genes needed)
all cells have same DNA makeup but some genes aren't expressed and some are, giving rise to specialised functions
regulation needed to see when gene should be expressed
respond to environment
leads to
CONTROL AT TRANSCRIPTIONAL LEVEL
level of control
expression of gene (expressed or not)
level of expression (high/low levels of expression)
note: basal transcription factors alone causes transcription at a low (basal) rate (ref. protein synthesis)
MECHANISM
specific transcription factors bind to control elements
far away (distal) from gene undergoing transcription
activators
bind to enhancer sequence
looping mechanism (and DNA bending proteins) brings
bound
activator near to transcription initiation complex
enhancer-activator complex interacts with transcription initiation complex to up-regulate transcription
rate of transcription increases
repressors
binds to silencer sequence
looping mechanism (DNA bending proteins) brings bound specific transcription factor near transcription initiation complex
allows repressor-silencer complex to interact with transcription initiation complex to down regulate transcription
decreases rate of transcription
eukaryotic vs prokaryotic (once it binds to silencer)
prokaryotic: repressors bind to operators, physically blocking RNA polymerase from binding to operator
eukaryotic:
block DNA binding site for an activator protein to prevent it from binding to an enhancer sequence
competitive DNA binding
silencer and enhancer sequence must be adjacent to one another (not needed for other types of genes with different control mechanisms)
activator binds to enhancer but repressor binds to and masks activation domain (ref structure of STF)
prevents formation of transcription initiation complex
Activation domain of repressor interacts with general transcription factors to block further assembly or prevent release of RNA polymerase
RNA polymerase can't move or TIC falls apart
package regions of eukaryotic chromosome into heterochromatin
recruiting repressive chromatin remodelling complex
as heterochromatin in transcriptionally inactive
recruit histone deacetylase to promoter for local histone modification
condenses chromatin into heterochromatin
less accessible to RNA polymerase and general transcription factors
STRUCTURE
DNA binding domain
recognises and allows binding to specific DNA sequence
Activation domain
interacts with other components of transcription machinery (transcription initiation complex)
combinational control
multiple enhancer and silencer sequence on gene
activation of that sequence depends on time, cell type, location
multiple activators and repressors (combination) creates a more significant effect
for precise control
only when appropriate activators or repressors are present will gene be silent/ expressed
leads to
CONTROL AT POST TRANSCRIPTIONAL LEVEL
splicing
alternative splicing controls what genes are expressed (or excised)
polyadenylation
affects half-life of RNA
more stable mRNA (longer half-life) allows it to remain in the cytoplasm longer
serves as a template for assembly of polypeptide more
increases amount of translation
5' capping
stablises mRNA (prevents digestion from 5' exonuclease)
mRNA can be a template for assembly of polypeptides more times (translated more times)
leads to
CONTROL AT TRANSLATIONAL LEVEL
occurs in the cytoplasm
level of expression (of mRNA) dependent on
Half-life of RNA
more stable mRNA (longer half-life) allows it to remain in the cytoplasm longer
serves as template for assembly of polypeptide more
increased by polyadenylation
decreased by specific proteins that bind to 3'UTR (3' untranslated region, directly after translation termination code)
proteins mark mRNA for rapid degradation - limits how many times mRNA can be used for translation
affected by hormones: stimulate or retard rate of degradation of mRNA
affect's mRNA's availability for translation to protein
repressors at initiation of translation
proteins mask mRNA so it can't be translated
repressers bind to 5' UTR of mRNA (upstream from initiation codon) prevents ribosome binding
steric (spatial arrangement) hindrance
eIF
(eukaryote initiation factors)
inhibitory proteins prevents formation of translation initiation complex
(initiator tRNA, mRNA, small and large subunit, initiation factors)
leads to
CONTROL AT POST TRANSCRIPTIONAL LEVEL
of newly formed polypeptides in cytoplasm
BIOCHEMICAL MODIFICATION
proteins form functional proteins through addition of biochemicals
glycosylation
addition of carbohydrates
forms cell surface glycoproteins
phosphorylation
add phosphate groups
activation of transcription factors
acetylation/methylation
eg. histones
hydroxylation
PROTEOLYTIC CLEAVAGE
of insulin (insulin maturation)
preproinsulin transcribed (110 amino acids)
removal of single peptide to produce proinsulin
formation of disulphide bond between A and B chains, removal of C chain
produces biologically active insulin molecule (51 amino acids)
PROTEIN DEGRADATION
cause
half-life of protein ends once it fulfils it's function
cells must be able to dispose of faulty or damaged proteins rapidly (prevent accumulation)
mechanism
proteins destabilised by chemical modification of N terminus
by ubiquitinylation
adds ubiquitin covalently to a target protein
marks protein for degradation by proteasome (protease complex)
allows for