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Year 2 Semester 1 > CMB2001 Control of Eukaryotic Gene Expression > Flashcards

CMB2001 Control of Eukaryotic Gene Expression Flashcards

1
Q

What is Gene expression?

A

Process by which information in genes (DNA) is decoded into protein.

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2
Q

What is transcription?

A

Transfer of genetic information from dsDNA to ssRNA (mRNA)

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3
Q

Describe the process of initiation of transcription in prokaryotes

A

-σ70 combines interacts with RNA polymerase, working together to recognise promoter regions and initiate transcription, forming an open complex.

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4
Q

After how many bases does σ70 detach?

A

~10 bases

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5
Q

What are promoters?

A

Cis acting DNA regulatory element through which transcription is initiated and controlled.

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6
Q

What are the regions that make up Eukaryotic promoters?

A

-Regulatory region
-Core (basal) region

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7
Q

Which region of eukaryotic promoters are further upstream?

A

Regulatory region

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8
Q

Name some core (basal) promoter elements

A

-TATA box
-Initiator (Inr)
-MTE (Motif ten element)
-DPE (Downstream core promoter element)
-BRE (TFIIB Recognition element)
-CpG islands

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9
Q

Describe what occurs when CpG islands are methylated?

A

They are silenced (ie transcription is switched off)

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10
Q

What class of eukaryote contains CpG islands?

A

Mammalia

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11
Q

Do Eukaryotic promoters have all elements?

A

NO

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12
Q

What is the UAS found in promoter regions?

A

Upstream activating sequence, an activator binding site

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13
Q

What is the URS found in promoter regions?

A

Upstream repressing sequence, A repressor binding site

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14
Q

What are the two tools to identify promoter elements?

A

-Sequence comparison
-Reporter analysis

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15
Q

What does sequence comparison of promoters consist of?

A

-Lining up sequences with known consensus sequences
-Helps identify key characteristics eg TATA boxes

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16
Q

What is the limitation with sequence comparison of promoters?

A

Does not tell us function and mechanism

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17
Q

What does reporter analysis of promoters consist of?

A

-Attach a regulatory sequence to a reporter gene
-Using regulatory sequence in question to express a “reporter” gene which is easy to measure in terms of quantity of expression

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18
Q

Give examples of reporter genes

A

-GFP
-Luciferase
-LacZ (β-galactosidase)

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19
Q

Why is the quantity of reporter protein significant?

A

Provides a measure of gene expression

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20
Q

What can reporter analysis be used to identify?

A

-When a gene is expressed
-Where it is expressed
-What signals it responds to
-What factors and sequences control its expression

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21
Q

Name some major eukaryotic RNA polymerases

A

-RNA pol I
-RNA pol II
-RNA pol III

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22
Q

What is the target gene of RNA pol I?

A

rRNA

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23
Q

Where is RNA pol I located?

A

In the nucleolus

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24
Q

What is the target gene of RNA pol II?

A

-mRNA
-snRNAs
-miRNAs

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25
Q

Where is RNA pol II located?

A

In the nucleus

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26
Q

What are the target genes of RNA pol III?

A

-tRNA
-5S RNAs
-U6 RNA
-7S RNA

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27
Q

How many subunits make up Eukaryotic RNA Pol II?

A

12 Subunits

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28
Q

Where is RNA pol III located?

A

In the nucleus

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29
Q

What are General Transcription Factors (GTFs)?

A

A set of factors that recruit RNA pol II to the promoter and direct initiation at the start-site

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30
Q

Name some Eukaryotic General transcription factors?

A

-TFIIA
-TFIIB
-TFIID
-TFIIE
-TFIIF
-TFIIH

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31
Q

Where do General Transcription Factors form a complex on?

A

TATA box

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32
Q

Describe the order of addition in the formation of the Pre Initiation Complex (PIC)

A

-IID binds
-IIA binds
-IIB binds
-RNA pol II and IIF binds
-IIH and IIE binds

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33
Q

What does the job of σ70 in eukaryotes?

A

General Transcription Factors (GTFs)

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34
Q

Describe Transcription initiation by RNA pol II

A

-Helicase activity of TFIIH separates template strand at start site
-As Pol II begins transcribingg it is extensively phosporylated on C-terminal domain

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35
Q

Describe the C terminal domain of RNA pol II

A

Series of repeats located at the C-terminal end of the largest subunit (β’ homologous)

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36
Q

What occurs to the General transcription factors as transcription is initiated?

A

-TFIID and TFIIA may stay behind
-TFIIB, TFIIE and TFIIH are released
-TFIIF move down the template with Pol II

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37
Q

Describe the function of TFIID and the number of subunits

A

-Binds to the TATA box
-Recruits TFIIB
13 subunits

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38
Q

Describe the function of TFIIA and the number of subunits

A

-Stabilises TFIID binding
-Anti repression function
3 subunits

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39
Q

Describe the function of TFIIB and the number of subunits

A

-Recruits RNA pol II-TFIIF complex
-Important for start site selection
1 subunit

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40
Q

Describe the function of TFIIF and the number of subunits

A

-Assists TFIIB in recruiting RNA pol II
-Stimulates RNA Pol II elongation
2 subunits

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41
Q

Describe the function of TFIIE and the number of subunits

A

-Helps recruit TFIIH and modulates TFIIH activity
2 subunits

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42
Q

Describe the function of TFIIH and the number of subunits

A

-Promotes melting and clearance
-CTD Kinase activity
-DNA repair coupling
9 subunits

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43
Q

Name the two parts of TFIIH GFT

A

Core and CAK

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44
Q

What is the function of the CAK module of TFIIH?

A

Contains one of the kinases that phosphorylates the CTD of RNAP II

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45
Q

What enzyme does TFIIH contain that melts promoters?

A

An ATPase called XPB or Ssl2

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46
Q

How does Ssl2 or XPB helices form open complexes?

A

-Uses energy from ATP hydrolysis to push DNA into the cleft where RNA polymerisation is catalysed
-Creating torsional stress that contributes to open complex formation

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47
Q

What does TFIID consist of?

A

TATA binding protein (TBP) and TBP associated factors (TAFs)

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48
Q

Describe the properties of TATA binding protein (TBP)?

A

-CAN direct assembly of the PIC on a TATA containing promoter
-CANNOT direct PIC on a TATA-less promoter
-CANNOT support “activated” transcription

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49
Q

What do TBP associated factors (TAFs) do?

A

-Promote the interaction of TFIID with basal promoter elements
-TAFs interact with activators to promote transcription initiation

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50
Q

What is an enhancer?

A

-DNA regions close or far from the start-site
-Binding sites for activator proteins

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51
Q

What are enhancers often composed of?

A

Multiple UAS elements

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52
Q

What are Silencers?

A

-DNA regions close or far from the start-site
-Binding sites for repressor proteins

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53
Q

What is the basal transcription machinery?

A

Another name for GTFs and RNA pol II

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54
Q

What is the Pre initiation complex?

A

Assembly of the basal machinery at the core promoter

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55
Q

What is an activator?

A

A factor that binds to gene specific regulatory sequences (ie UAS & Enhancer elements) and stimulates
transcription initiation.

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56
Q

How is transcription controlled?

A

By changing the efficiency of the Pre Initiation Complex

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57
Q

What are the classes of UAS/enhancer elements?

A

-Common sequence elements
-Response elements

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58
Q

Describe Common sequence enhancer elements

A

-Often located close to the core promoter
-Bind activators that are relatively abundant in the cell and constantly active

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59
Q

Describe Response enhancer elements

A

-Bind factors whose activity is controlled in response to specific stimuli

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60
Q

Give an example of a response enhancer element

A

-SRE binds to serum response factor, and is induced by Growth factors
-HSE binds to Heat shock factor, and is induced by Heat shock

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61
Q

What is combinatorial control of transcription?

A

The type and combination of elements dictates when and at what level a gene is transcribed.

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62
Q

How close do enhancers have to be to ORF to work?

A

Enhancers work irrespective of location or orientation

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63
Q

How can enhancers work at any location or orientation?

A

Activators associated with Enhancer elements are brought into contact with GTF/RNA Pol II sat the core looping out intervening DNA

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64
Q

How cab eukaryotic activators work when separated?

A

-Eukaryotic activators are modular
-Working even when separated
-They often are separated

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65
Q

What are the domains found in Eukaryotic activators?

A

-Activation domains
-DNA binding domain
-Flexible protein domain often joining these

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66
Q

How may we manipulate Eukaryotic activators?

A

-We may combine modules from different activators
-eg the activation domain of one activator with the DNA binding domain of a different activator

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67
Q

Give some examples of DNA binding domains

A

-Leucine zipper
-Zinc finger
-Homeodomain
-Helix loop helix

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68
Q

Name some characteristics of activation domains

A

-Often characterised according to amino acid composition
-Lack of sequence conservation
-Generally thought to be unstructured
-Contain multiple short segments that work together in an additive fashion
-Interact with other proteins in the transcriptional machinery

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69
Q

Give some in vitro approaches to analysing activators

A

-DNA foot printing
-Electrophoretic mobility shift assays (gel shift)
-Transcription assays

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70
Q

Give some in vivo approaches to analysing activators

A

-Reporter assays
-Chromatin immunoprecipitation

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71
Q

Describe electrophoretic mobility shift assays (gel shift) as a method to analyse activators

A

-Measures ability of a protein to bind to a certain DNA sequence
-Combine activator with radiolabelled probe DNA, then run this on non denaturing acrylamide gel.

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72
Q

Describe transcription assays as a method to analyse activators

A

-Mix RNA Pol II, GTFs, DNA template and radiolabelled rNTPs.
-Measuring RNA transcript

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73
Q

What do transcription assays to analyse activators require?

A

-Requires the activator to both have a functional DNA binding domain and a functional activation domain

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74
Q

Describe Reporter assays as a method to analyse activators

A

-Producing a plasmid with a gene encoding protein X
-Producing a plasmid with a X binding site and reporter gene
-Measuring level of reporter gene expressed

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75
Q

Give the method for chromatin immunoprecipitation

A

-Cross link bound proteins to DNA
-Isolate chromatin
-Precipitate chromatin with protein-specific antibody
-Reverse cross link and digest protein
-Analyse the DNA using PCR or sequencing

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76
Q

How do activators work?

A

-Promote binding of an additional activator
-Stimulate complex assembly, with activators interacting with TFIIB which aid TFIID binding to the TATA box
-Release Stalled RNA polymerase
-Modulate chromatin

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77
Q

Describe the composition of activation mediators

A

-Approximately 22 polypeptides
-Can exist on its own or associated with RNA pol II (through the C terminal domain)
-Composed of Head, Middle and Tail domains

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78
Q

What are the function of activator mediators?

A

-Many activators interact with specific mediator subunits
-Mediator provides a bridge between activators and RNA pol II
-Mediator activator interactions aid recruitment of RNA pol II and enhance PIC formation

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79
Q

Where may RNA polymerases stall, and how is this solved?

A

RNA pol II can stall at or near to the promoter, which active activator proteins releasing stalled RNA pol II

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80
Q

What is the basic function of chromatin?

A

To compact DNA

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81
Q

What is the composition of Chromatin?

A

Primarily of small basic proteins called histones

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82
Q

What are the two basic types of histones?

A

Core and Linker histones

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83
Q

What are core histones split into?

A

-Globular domain made up of ⍺ helices and loops
-N terminal tail which are highly basic, rich in Lys and Arg

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84
Q

What are the repeating units of core histones?

A

Nucleosomes

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85
Q

Describe the composition of a nucleosome

A

147bp of DNA wrapped twice around an octamer of histone proteins

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86
Q

Describe the composition of the histone octamer formed in a nucleosome?

A

Central H3-H4 tetramer + 2 flanking H2A-H2B dimers

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87
Q

How are nucleosomes organised?

A

-DNA passes directly from one nucleosome to the next
-Linker histones such as histone H1 bind to the DNA between nucleosomes
-In vitro linker histones result in the formation of a thicker 30nm fibre

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88
Q

What evidence is there that chromatin inhibits transcription?

A

-In vitro reconstitution experiments
-In vivo nucleosome positioning experiments
-Genetic studies in budding yeast

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89
Q

Describe in vitro reconstitution experiments that demonstrate that chromatin inhibits transcription

A

-RNA pol II + transcription factors + naked DNA template = Transcription
-RNA pol II + transcription factors + chromatin template = No transcription

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90
Q

Describe in vivo nucleosome positioning experiments that demonstrate that chromatin inhibits transcription

A

Numerous experiments have shown that nucleosomes are disrupted or lost during transcriptional activation

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91
Q

Describe the genetic studies in budding yeast that demonstrate that chromatin inhibits transcription

A

Nucleosome depletion is linked to the expression of many inducible genes

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92
Q

What mechanisms may cells use the modulate the dynamic structure of Chromatin?

A

-Histone variants
-Post translational modification of histone
-ATP dependent chromatin remodelling

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93
Q

Describe how histone variants may modulate chromatin structure

A

-Histone variants differ from highly conserved major types
-Expressed at very low levels
-All conventional (except H4) have variants
-Histone variants creates new structural and functional properties of the nucleosome which affect chromatin dynamics.

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94
Q

Give some examples of post-translational modification of histones

A

-Acetylation
-Methylation
-Ubiquitylation
-Phosphorylation

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95
Q

How may post translational modification of histones modulate chromatin?

A

-Histone modification state has been proposed to involve a code that sets its transcriptional state BY
-Directly altering chromatin folding/structure
-Could control the recruitment of non histone proteins to chromatin

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96
Q

What enzymes are involved in the acetylation of histone lysines?

A

Histone acetyl transferases (HATs)

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97
Q

What enzymes are involved in the deacetylation of histone lysines?

A

Histone decatylases (HDACs)

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98
Q

How may chromatin be acetylated?

A

Through Histone Lysine acetylation

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99
Q

Is acetylation a key component in transcriptional activation or silencing?

A

ACTIVATION

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100
Q

What are the two types of multisubunit complexes of Histone Acetyl transferases (HATs)?

A

GNAT family and MYST family

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101
Q

How are HATs recruited?

A

-Activators recruit HATs to specific promoters
-Many HAT complexes contain a specific subunit that interacts with activators
-Also some HATs are part of the general transcription machinery

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102
Q

How does acetylation mediate transcriptional activation?

A

-Direct influence on chromatin structure, as it causes the conversion of charged N termini to uncharged termini, causing histones to be exposed
-Directs the recruitment of BROMODOMAIN proteins, which often promote transcription

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103
Q

Where can histone methylation occur?

A

On Lysine and Arginine residues on histones

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104
Q

What enzymes are responsible for Histone methylation?

A

Histone Lysine Methyl transferases (HKMTs)

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105
Q

What enzymes are responsible for Histone demethylation?

A

Lysine Demethylases

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106
Q

How do HKMTs differ from HATs?

A

They may mono, di or tri methylate a lysine

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107
Q

Does methylation have a large effect on chromatin structure?

A

It does not affect charge so probably has only minor if any influence on chromatin structure

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108
Q

Are methyl-lysine residues on histones activators or repressors?

A

Depending on context they may do either, eg
-H3 Lys9 represses
-h3 Lys4 activates

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109
Q

Give some examples of environmental challenges that a cell may respond to?

A

-DNA damage
-Infection
-Hypoxia
-Physical stress

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110
Q

Give some cellular responses that may occur in response to environmental changes

A

-Gene expression
-Programmed death
-Repair
-Immune response

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111
Q

Give some pathways that allow the cell to respond to environmental changes

A

-NFκB
-p53
-HIF

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112
Q

What does NFκB stand for?

A

Nuclear Factor of the kappa Immunoglobulin light chain in B cells

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113
Q

What does the NFκB pathway allow for?

A

-Cells to respond to external challenges or threats
-By regulating expression of certain genes

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114
Q

What are the two subunits that make up the Mammalian NFκB family?

A

-RelA
-p50
-RelB
-c Rel
-p105
-p100
-p52

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115
Q

What region of DNA encodes DNA binding in NFκB?

A

Rel Homology domain

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116
Q

What region of DNA encodes the dimerisation functions of NFκB?

A

Rel Homology domain

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117
Q

How are p50 and p52 produced (NFκB)?

A

They are proteolytically processed from their precursor proteins p105 and p100

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118
Q

What do ankyrin repeats in p100 and p105 allow for?

A

To function as IκB like inhibitors

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119
Q

What is E3 Ubiquitin ligase responsible for?

A

Attachment of ubiquitin chains to a target protein

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120
Q

What is the Ubiquitin proteasome pathway responsible for?

A

Protein degradation

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121
Q

Describe what occurs after a chain of 5 ubiquitin molecules are attached to a protein substrate?

A

The 26S proteasome recognises this, and the protein is digested to peptides.

122
Q

What induces NFκB?

A

-Inflammatory cytokines
-Bacterial products
-Viral proteins and infection
-DNA damage
-Cell stress

123
Q

What does NFκB regulate?

A

-Immune and inflammatory responses
-Stress responses
-Cell survival and cell death
-Cell adhesion
-Proliferation

124
Q

What makes up the NFκB complex?

A

-p50 + RelA dimer (interact with DNA)
-IκB (inhibitor protein)

125
Q

Describe the process whereby NFκB is activated?

A

-Ligand is exposed to cell
-IKK kinase is activated, phosphorylating IκB kinase complex
-This complex phosphorylates IκB, which is then ubiquinated
-IκB is proteolytically degraded
-NFκB translocates to nucleus

126
Q

What are the three core subunits of the IκB Kinase (IKK) complex?

A

IKKγ (regulatory), IKK⍺ (catalytic), and IKKβ (catalytic)

127
Q

Name some inhibitors of NFκB

A

-IκB⍺
-IκBβ
-IκBε
-Bcl 3

128
Q

What is the action of IκB?

A

It inhibits NFκB

129
Q

What is the same in both the canonical and non canonical pathway in the activation of NFκB?

A

Ubiquitination, proteasomal degradation and nuclear localisation of NFκB complex

130
Q

Give some inducers of the canonical pathway to activate NFκB

A

-TNF
-IL1
-LPS

131
Q

Give some inducers of the non-canonical pathway to activate NFκB

A

-LPS
-CD40
-LMP1

132
Q

Give some diseases associated with improper NFκB functioning

A

-Cancer
-Arthritis
-AIDS
-Asthma
-Diabetes
-Artherosclerosis

133
Q

How many activators/modulators of NFκB are there?

A

> 200

134
Q

How does diversity in genes benefit the NFκB system?

A

A multigene family composed of dimers allows the formation of many different types of NFκB dimers with different properties.

135
Q

How do different subunits of NFκB allow for different properties and functions?

A

Different subunits have subtly different DNA binding specificity and so can target different genes and position themselves on DNA.

136
Q

What may conjugate NFκB after it has been translocated to the nucleus (to regulate)?

A

-Kinases
-Acetylases
-Phosphatases

137
Q

What may regulate NFκB after it has been translocated to the nucleus?

A

-Corepressors
-Coactivators
-Heterologous transcription factors

138
Q

How can we regulate NFκB’s activity in the nucleus?

A

-Transcriptional repression
-Transcriptional activation
-Promoter targeting and selectivity

139
Q

How may NFκB gain access to NFκB-dependent genes hidden by their chromatin state?

A

NFκB can recruit chromatin remodellers or rely on other proteins to change the state

140
Q

What levels of regulation combine to give transcriptional specificity when NFκB is stimulated?

A

-Phosphorylation and degradation of IκB⍺, IκBβ or IκBε
-Translocation of NFκB to the nucleus and modification of subunits
-DNA binding and gaining access to promoter/enhancer (chromatin remodelling and cooperative DNA binding with other transcription factors_
-Transactivation, the interaction with the basal transcription complex and coactivators

141
Q

How may COVID19 affect NFκB regulated genes, affecting symptoms and prognosis?

A

-May affect levels of expression in IFNβ cells
-INCREASING INFLAMMATION
-Decreasing relative anti-viral properties

142
Q

What is the function of beta interferon (IFNβ)?

A

If unregulated, and IFNβ are multimerised, they can act as a viral inducible promoter and respond to other inducers.

143
Q

How may NFκB act in a coactivator interaction surface?

A

It participates in a “combination lock”, with only the p50/RelA dimer working at the IFNβ enhancer.

144
Q

Where do coactivator complexes favourably form?

A

At the promoters and enhancers where an appropriate interface is required.

145
Q

How may NFκB directly induce transcription after chromatin remodelling?

A

By recruiting the BTM - Basal transcription machinery

146
Q

How may the alternative (non-canonical) pathway differ from the classical (canonical) pathway with NFκB?

A

Phosphorylation of the p100 subunit leads to proteolytic processing to p52

147
Q

How can activation of gene transcription with NFκB be likened to a combination lock.

A

Each number of the combination lock is a different TF, or specifically modified TF or chromatin remodelling factor. It is only when all the numbers of the combination are entered correctly (ie all the TFs etc are recruited to the gene promoter/enhancer) that the lock is opened (that is transcription occurs).

148
Q

How may parallel signalling pathways regulate the transcriptional specificity found in NFκB?

A

Parallel signalling pathways (e.g. kinases) also active in the cell can regulate each of these steps. For example, by phosphorylating NFκB subunits or activating other transcription factors that work co-operatively or antagonistically with NFκB

149
Q

What environmental challenge activates the p53 pathway?

A

DNA damage

150
Q

What environmental challenge activates the HIF pathway?

A

Hypoxia

151
Q

What is Hypoxia

A

Hypoxia can be defined as a lowering of the O2 = concentrations compared to the normal levels cells are exposed to

152
Q

What may the hypoxia response be used for in embryonic development?

A

Development in
-Placenta
-Heart
-Bone
-Vasculature

153
Q

What may the hypoxia response be utilised to adapt to?

A

-High altitude living
-Intense muscle exercise

154
Q

What diseases may hypoxia be related to?

A

-High altitude diseases
-Stroke/Ischemia
-Neurodegenerative diseases
-Ageing
-Cancer
-Rheumatoid arthritis
-Schizophrenia

155
Q

How do cells respond to hypoxia?

A

-Restoration of oxygen homeostasis
-Cell survival
-Cell death

156
Q

Through what pathways may cells respond to Hypoxia?

A

-Transcriptional program (HIF)
-Translational block
-Chromatin structure changes
-DNA replication block
-microRNA signature

157
Q

What is HIF?

A

-Hypoxia Inducible Factor
-Heterodimeric transcription factor (HIF-⍺ and HIF-1β)

158
Q

What subtypes is there for the HIF-⍺ subunit?

A

-HIF-1⍺ Which is ubiquitously expressed in all tissues
-HIF-2⍺ Which is restricted to certain tissues
-HIF-3⍺ Which is restricted to certain tissues and functions as a dominant negative inhibitor for 1 and 2.

159
Q

What is the ODD region found in the HIF subtypes genome?

A

The oxygen dependent degradation domain

160
Q

What regulates the function of HIF?

A

Proline hydroxylases (PHD)

161
Q

What do Proline hydroxylases require?

A

Oxygen, meaning in an anoxic state they will not inhibit HIF

162
Q

What do Proline Hydroxylases do in the presence of oxygen?

A

-PHDs hydroxylate prolines on HIF1⍺
-Allowing binding sites for VHL
-Which binds to HIF1⍺ and leads to ubiquitation

163
Q

How is HIF1⍺ regulated on multiple levels?

A

-HIF1⍺ mRNA evades block on translation
-Lack of oxygen inactivates the PHD proteins

164
Q

What happens to HIF1⍺ in hypoxia?

A

In hypoxia, PHDs and FIH are inhibited, and HIF-1α is stabilized and able to dimerize with HIF-1β and activate target gene transcription through recruitment of co- activators.

165
Q

What pathways does HIF control?

A

-Oxygen supply
-Transcription
-Cellular metabolism
-Cell death
-HIF control
-Cell growth

166
Q

What may occur to hypoxic tumours?

A

-Activation of HIF stimulates angiogenesis, bringing nutrients and oxygen to the tumour
-It also leads to increased evasion and metastasis

167
Q

What environmental challenge activates the p53 pathway?

A

DNA damage

168
Q

Give some domains found in p53

A

-Transactivation domain
-Proline rich domain
-Nuclear localisation sequence
-Tetramerisation domain

169
Q

How may NFκB, p53 and HIF interact?

A

-Many functions overlap
-Depending on context they may either function cooperatively or antagonistically

170
Q

What inactivates p53?

A

Its regulator, Mdm2

171
Q

What change happens to p53 if activated?

A

Dissociation with its negative regulator, Mdm2

172
Q

What occurs when p53 is separated from Mdm2?

A

p53 will either
-induce a cell cycle to allow repair and survival before restarting the cycle
-Apoptosise the cell, eliminating damaged cells

173
Q

What is the role of p14 ARF?

A

-Tumour suppressor with expression induced by oncogenes as a result of increased cellular proliferation
-Disrupts the interaction between the p53 tumour suppressor and Mdm2

174
Q

How does p14 ARF disrupt the interaction between p53 and Mdm2?

A

ARF binds Mdm2 and inhibits its ubiquitin ligase activity

175
Q

How does Mdm2 function?

A

-It is an E3 ubiquitin ligase
-Promotes ubiquitation of p53
-leading to degradation by the proteasome

176
Q

How does DNA damage lead to p53 and Mdm2 separating?

A

p53 is phosphorylated at serine 15 by the ATM or ATR kinases, and Mdm2 is phosphorylated, disrupting their interaction

177
Q

What do cancer cells do in reaction to p53?

A

They will activate/inhibit the p53 either by
-Mutating ARF
-Mutating ATM
-Mutating p53
-Amplifying Mdm2

178
Q

How do prokaryotic and eukaryotic transcription and translation differentiate?

A

-Prokaryotic transcription and translation is coupled
-Eukaryotic transcription and translation are separate

179
Q

At what levels can eukaryotic gene expression be regulated?

A

-Transcription control
-RNA processing control
-Translational control
-Protein activity control

180
Q

Name some features added to eukaryotic mRNA post transcription

A

-m7G cap
-PolyA tail

181
Q

Are m7G caps and PolyA tails encoded in the genome?

A

NO

182
Q

What modifications to pre mRNA occur after transcription

A

-Capping
-Splicing (alternative splicing)
-Polyadenylation
-Editing

183
Q

Describe the steps involved in synthesis of the m7G cap

A

-GpppN structure is formed
-Methylation occurs, altering chemical behaviour

184
Q

What are the functions of the m7G cap?

A

-Protects mRNA from degradation by 5’-3’ nucleases
-Facilitates splicing
-Facilitates export from the nucleus
-Critical for translation of most mRNAs

185
Q

What mediates the functions of the m7G cap?

A

-CBP80/CBP20 in nucleus
-elF4 complex is cytoplasm

186
Q

What conserved sequences are found in exon and intron boundaries?

A

-5’ splice site
-3’ splice site
-Branch site

187
Q

What do the conserved sequences in introns do?

A

Recruit the splicing machinery required to remove the intron and join the exons

188
Q

Describe the steps in the splicing of introns

A

1 - Cut at 5’ splice site
- Creating a bond between 5’ end of intron and branch site
2 - Cut at 3’ splice site to release intron lariat
- Ligation of two exons

189
Q

Through what kind of reaction are introns spliced?

A

Transesterification

190
Q

What is the spliceosome?

A

-Enzymatic complex that catalyses the removal of introns
-Requiring ATP
-Large complex containing over 200 proteins

191
Q

Give some examples of proteins in the spliceosome

A

-RNA binding proteins
-ATPases
-GTPases
-snRNPs

192
Q

What are snRNPs?

A

Small nuclear ribonucleo-protein particles

193
Q

What do snRNPs do?

A

catalyse splicing

194
Q

Do snRNPs code for a protein enzyme?

A

-No they do not, they are non coding DNA.
-They form a stable RNA-protein complexes in the nucleus

195
Q

What is alternative splicing?

A

The process where exons from the same gene are joined in different combinations, leading to different mRNA transcripts

196
Q

Give some examples of types of alternative splicing

A

-Exon skipping
-Intron retention
-Mutually exclusive exons
-Alternative 5’ or 3’ site

197
Q

What do activators bind to to regulate alternative splicing?

A

Intronic and Extrinsic splicing enhancers

198
Q

What do repressors bind to to regulate alternative splicing?

A

Intronic and Extrinsic splicing silencers

199
Q

What is polyadenylation?

A

The addition of a polyA tail at the 3’ end of mRNA

200
Q

What is polyadenylation initiated by?

A

The polyadenylation signal, a sequence of AAUAAA 10-35 nucleotides upstream of the polyA site.

201
Q

What proteins are required for polyadenylation?

A

-Cleavage and Polyadenylation specificity factor (CPSF)
-Cleavage stimulatory factor (CstF)
-Poly(A) polymerase

202
Q

What occurs after the polyadenylation signal is bound to?

A

-Endonuclease cleavage
-Addition of As by PolyA polymerase

203
Q

What is upstream of the polyadenylation signal?

A

U-rich upstream element (USE)

204
Q

What is downstream of the polyadenylation signal?

A

G/U or U rich tract just downstream of polyA site

205
Q

What is the significance of the polyA tail?

A

-All mRNAs have 3’ polyA tail
-Enhances export of RNA
-Enhances translation
-Stabilises the 3’ end of the mRNA

206
Q

What is RNA editing?

A

Nucleotide alterations which result in different or additional nucleotides in the mature RNA

207
Q

What are the three major classes of RNA, of which RNA editing occurs?

A

mRNA, tRNA and ribosomal RNA

208
Q

What are the two classes of RNA editing?

A

-Insertion/deletion
-Modification

209
Q

Give some examples of types of base modification in RNA editing

A

-Marked nucleotide
-Altered identity

210
Q

What is marking a nucleotide in base modification in RNA editing?

A

-Addition of methyl group, changing the type of proteins that may bind

211
Q

What is altering identity in base modification in RNA editing?

A

Changing groups on a base (eg NH2 for O)

212
Q

What is RNA editing by deamination?

A

-Through enzymatic deamination
-Inosine is recognised as guanine, therefore this is equivalent to an A to G change.

213
Q

Are all classes of RNA exported from the nucleus by the same pathway?

A

NO! They each have different pathways

214
Q

How can mRNA be changed in terms of location?

A

RNA can be distributed in higher concentrations to certain areas of the cell

215
Q

Why localise mRNA?

A

-Localise protein synthesis
-Generate cell polarity
-Prevent expression in the wrong place
-Local control of translation
-Promotes efficiency of subsequent protein targeting

216
Q

Describe diffusion based RNA localisation

A

mRNAs freely diffuse in the cytoplasm and are locally entrapped by anchor proteins

217
Q

Describe Active transport based RNA localisation

A

-mRNA recognised by specific trans acting factors in the nucleus
-Cytoplasmic factors ensure transport along a polarised cytoskeleton

218
Q

How much of a ribosome is protein and RNA?

A

1/3 Protein, 2/3 RNA

219
Q

What does R represent in tRNA?

A

Purine (G or A)

220
Q

What does Y represent in tRNA?

A

Pyrimidine

221
Q

What does ᴪ represent in tRNA?

A

Pseudouridine

222
Q

Describe tRNA charging

A

1 - Amino acid activation. Amino acid and ATP bind catalytic site, nucleophilic attack by carboxylic acid oxygen yielding aminoacyl-adenylate
2 - Hydroxyl group of adenine 76 of tRNA attacks the carbonyl carbon of the adenylate, forming aminoacyl tRNA and AMP

223
Q

Where are tRNAs present in ribosomes?

A

Polypeptide chain site (P) and Aminoacylated tRNA binding site (A)

224
Q

What is the role of Factor G (eEF2 in eukaryotes)?

A

Hydrolyses GTP, catalysing mRNA movement across the ribosome

225
Q

What is the role of the 5’ cap on mRNA?

A

-Eukaryotic translation initiation depends upon this
-Small subunit binds to cap, scans the first AUG, encoding the initiating methionine of the protein
-Ternary complex binds, forming the 43s pre initiation complex

226
Q

What is the purpose of circularising mRNA when translation is initiated?

A

-Moniters integrity of mRNA
-Brings ribosomes ending translation close
-Several other key translation factors

227
Q

At what points is translation regulated?

A

-Formation of EIF4F
-43S binding
-Function of EIF2B
-Ternary complex formation

228
Q

What is required for 43S association with mRNA?

A

-eIf3 interacting with eIF4G
-RNA unwinding most 5’ UTRs have at least some structure

229
Q

What is the function of EIF2B?

A

-Its activity governs level of active EIF2-GTP and this overall initiation rate
-EIF2B activity is down regulated in response to stresses
-Impairs generation of ternary complex, reducing translation initiation of mRNA

230
Q

How is EIF2B regulated?

A

Through EIF2 phosphorylation, which competitively inhibits eIF2B

231
Q

What are the three subunits of eIF2?

A

eIF2⍺ - Phosphorylated on Ser51 by PKR, PERK, GCN2 HRI
eIF2β - binds eIF2B, eIF5
eIF2γ - GTPase, Met-tRNA

232
Q

Name some eIF2 kinases

A

-PKR
-PERK
-GCN2
-HRI

233
Q

What is eIF2 kinase PKR activated by?

A

double stranded RNA (Viral infection), inhibiting translation initiation

234
Q

What is eIF2 kinase PERK?

A

A mediator of the unfolded protein response (endoplasmic reticulum stress), inhibiting translation initiation

235
Q

What is eIF2 kinase GCN2?

A

A regulator of translation in response to amino acid availability, inhibiting translation initiation

236
Q

What is the function of eIF2 kinase HRI?

A

Linking global availability to protein synthesis

237
Q

Describe eIF2 kinase PKR

A

-PKR expression increases when cells are exposed to interferons
-Which are produced and released by cells infected by viruses
-When PKR binds dsRNA it dimerises and is activated

238
Q

What is the function of UTRs in mRNA?

A

-Untranslated regions
-Influence stability in mRNA

239
Q

What are Iron response elements (IREs)?

A

-Hairpin loops with a conserved loop sequence and a bulge within the stem
-Found in the 5’ or 3’ UTRs of iron regulated mRNAs
-Bound by Iron Regulatory proteins (IRP1 and IRP2)

240
Q

What are iron response elements bound by?

A

Iron regulatory proteins (IRP1 and IRP2)

241
Q

What metal can be linked to regulation of gene expression?

A

Iron

242
Q

Why degrade RNA?

A

-To remove damaged mRNA
-To remove incorrectly transcribed mRNA
-To control gene expression

243
Q

Give an example of how a hormone can influence mRNA degradation

A

-Casein mRNA increases on stimulation by prolactin (70 fold)
-But transcription only increases 2 fold
-As half life increases dramatically in response to prolactin as PolyA tail length increases

244
Q

Describe eukaryotic mRNAs during translation

A

-Circular
-This monitors mRNA integrity (will not be circular if it has lost cap or polyA)
-Brings ribosomes ending translation close to the AUG

245
Q

What does most decaying mRNA decay from?

A

Deadenylation-dependent decay

246
Q

As the polyA decays, what degrades the mRNA?

A

The exosome

247
Q

As the M7G cap is degraded, what degrades the mRNA?

A

XRN1

248
Q

Give some examples of mRNA decapping enzymes

A

-DCP1
-DCP2

249
Q

Give some examples of mRNA deadenylase enzymes

A

Ccr/Not Complex

250
Q

Give some examples of mRNA endonuclease enzymes

A

-Argonaute
-Swt1
-Smg6

251
Q

Describe the mRNA exosome?

A

-3’ to 5’ exonuclease
-Multisubunit complex
-Involved in RNA turnover and processing
-RRP6 and RRP44 nuclease
-Rest of the subunits function in RNA binding and unwinding

252
Q

Describe XRN1

A

-5’ to 3’ exonuclease
-Involved in RNA turnover and processing
-Also involved in transcription termination

253
Q

What stimulates deadenylation dependent decay?

A

By certain sequences, strands, etc

254
Q

Give some examples of routes of stimulation of deanylation-dependent decay

A

-AU rich element or ARE
-Nonsense codon
-miRNA
-C for major coding deterinant
-miRNA recognition site

255
Q

Describe nonsense mediated decay of deadenylation-dependent decay.

A

-Mistakes in RNA are detected, and RNA is targeted for degradation
-As premature stop codons occur
-Exon junction complexes are not removed from downstream, which interact with RNA degradation machinery

256
Q

Give examples of how premature stop codons (PTCs) can be introduced

A

-Transcription
-Splicing
-Editing
-Polyadenylation
-Mutations

257
Q

What is siRNA?

A

Small inhibitory RNA

258
Q

What is RNAi?

A

RNA interference

259
Q

What is miRNA?

A

Micro RNA

260
Q

What is RISC?

A

RNA induced silencing complex

261
Q

Describe siRNAs

A

-21-23 nucleotide RNAs
-Perfect complimentary to target RNA
-Thought to be mainly viral defence mechanism
-Leads to the degradation of the target RNA

261
Q

Describe the transition in the formation of open complex from closed complex during transcription initiation in prokaryotes

A

CLOSED:
-RNA polymerase holoenzyme binds to the promoter region, which contains -35 TTGACA and -10 TATAAT box upstream of transcription start site, of which the σ factor binds to. DNA is double stranded.

OPEN:
-σ factor facilitates melting of the DNA helix around the -10 region, exposing the template strand. RNA polymerase stabilises the melted DNA by forming a transcription bubble.

262
Q

Describe miRNAs

A

-21-23 nucleotide RNAs
-Imperfect complimentary to target RNA
-Key gene regulatory mechanism in the cell
-Leads to block in translation

262
Q

Where are UAS or URS regions found?

A

In the regulatory region of eukaryotic promoters

263
Q

Describe how siRNA works

A

-RISC recognises the siRNA duplex and loads it
-RISC removes one of the siRNA strands “passenger:
-The remaining “guide” strand binds to the RISC and guides it to the target mRNA
-siRNA-RISC complex cleaves the target mRNA, causing degradation

263
Q

What are the subunits that make up bacterial RNA polymerase?

A

-β
-β’
-⍺ x 2
-𝜔

264
Q

Describe how miRNA works

A

-miRNA controls gene expression
-By binding to the mRNA in the cytoplasm
-This marks the mRNA for degradation by Argonaute protein

264
Q

Describe the pre initiation complex

A

CONSISTS OF
-RNA Polymerase
-General transcription factors including
-TFIID
-TFIIA
-TFIIB
-TFIIF
-TFIIH

265
Q

Describe different examples of 3’ UTR length changes?

A

-During embryonic development 3’ UTRs frequently get LONGER
-mRNAs in proliferating cells tend to have shorter 3’ UTRs

265
Q

Give the functions of the Pre Initiation Complex

A

-Promoter recognition
-DNA unwinding
-RNA polymerase II positioning
-Transition to the open complex
-C terminal domain phosphorylation

266
Q

What drives differing 3’ UTR length changes?

A

Alternate polyadenylation sites

266
Q

Name some activation domains

A

-Acidic patch (clusters of -ve charged residues)
-Glutamine rich (high glutamine content)
-Proline rich

267
Q

What is the benefit of longer 3’ UTRs?

A

More possibility of binding sites for miRNAs

267
Q

Describe the composition of activator mediators

A

-Consists of ~22 polypeptides
-Can exist on its own or associated with RNA pol II
-Composed of 3 domains: Head, Middle and Tail

268
Q

Describe the structure of core histones

A

-N terminal tail (highly basic)
-Globular domain (⍺-helices and loops)

269
Q

Give the key superfamily involved in ATP-dependent chromatin remodelling

A

SWI2/Snf2 ATPase superfamily

270
Q

Describe ATP dependent chromatin remodelling

A

-Utilises energy from ATP hydrolysis to change interactions between DNA and histones
-Either relaxes chromatin (forming euchromatin) or condenses (forming heterochromatin)

271
Q

Give some mechanisms of chromatin remodelling

A

-Nucleosome sliding (repositioned along DNA, exposing certain DNA regions)
-Ejection (removing entire histone octamers)
-Histone variant exchange (swapping histones)
-DNA unwrapping (making specific sequences more accessible)

272
Q

Describe the SWI/SNF class of ATP-dependent chromatin remodelling complex

A

-Uses energy from ATP hydrolysis to track along DNA and induce torsion
-Promotes nucleosome sliding and ejection, facilitating activation

273
Q

What may mutations in the SWI/SNF class of ATP-dependent chromatin remodelling complex result in?

A

-Mutations in the genes encoding subunits of the SWI/SNF complexes are collectively present in nearly 25% of cancers
-As it also acts as a tumour suppressor

274
Q

What factors may be involved in manipulating recruitment of chromatin in order to repress transcription?

A

-Histone Deacetylases
-ATP dependent remodellers
-Histone methylases

275
Q

Give the 4 major groups of histone deactylases

A

-Classical HDACs (zinc dependent)
-Class III Sir2 family (NAD dependent)

276
Q

What are the two types of chromatin, and describe them

A

-Euchromatin (gene rich, with potential to be transcribed)
-Heterochromatin (gene poor, with repetitive regions, associated with transcriptional silencing), examples include centromeres and telomeres

277
Q

Give some biochemical features of heterochromatin

A

-Hypoacetylation
-Specific histone H3 methylation
-Association of specific silencing factors

278
Q

What do chromodomain proteins often bind to?

A

Methylated lysine residues on heterochromatin

279
Q

Give a key chromodomain protein, and its function

A

-Heterochromatin Protein 1
-Forms and maintains heterochromatin
-Compacts nucleosomal arrays

280
Q

What are barr bodies

A

-Condensed, inactivated structures formed by one of the X chromosomes in females assembling into a specific form of heterochromatin
-Formation is controlled by non coding RNAs Xist and Tsix

281
Q

How may covid-19 lead to hypoxia?

A

-Acute respiratory distress syndrome (ARDS) caused by filling alveoli with inflammatory liquid
-Damage to pulmonary vasculature
-Impaired oxygen diffusion
-Hyperactivation of the immune system
-Haemoglobin and oxygen transport dysfunction

282
Q

Give examples of negative feedback in transcription factor pathways

A

-p53 induces its inhibitor Mdm2, which causes its proteolytic degradation
-HIF1⍺ induces the PHD proteins, which causes its proteolytic degradation
-NFκB induces its inhibitor IκB⍺ that removes it from the nucleus and retains it in the cytoplasm

283
Q

How do cancer cells and p53 interact?

A

Almost all cancer cells find ways to inactivate p53, or regulators of p53

284
Q

Describe Li-Fraumeni syndrome

A

-LFS is a hereditary genetic condition
-Caused by mutation in gene coding for p53

285
Q

Describe how p53 and NFκB may cross talk

A

-May suppress each other (eg by upregulating IκB⍺, or inducing MDM2)
-Both may bind to promoters of target genes involved in apoptosis, cell cycle regulation and inflammation
-Share modulators (CBP, ATM/ATR kinases, ROS)

286
Q

What is dystrophin linked to?

A

Duchenne muscular dystrophy

287
Q

Give some diseases associated with mutations causing defects in mRNA splicing

A

-Spinal muscular atrophy
-Retinitis pigmentosa
-Myotonic Dystrophy

288
Q

What is RNA editing involved in in medicine and development?

A

-Disease (eg atherosclerosis)
-Brain function
-Development
-Parasites

289
Q

Give some effects of mRNA editing

A

-Creation of start codons (by inserting U)
-Creation of new open reading frames by nucleotide insertion
-Changes in encoded amino acids and splice site choice
-Creation/removal of stop codons

290
Q

What is cytidine deamination of apoB protein?

A

Pre-mRNA editing where a cytidine is deaminated to uridine by APOBEC1 enzyme, forming two different forms of the apoB protein

291
Q

Name which type of ribosome is prokaryotic and eukaryotic

A

Prokaryotic = 70S
Eukaryotic = 80S

291
Q

Describe the steps of translational elongation

A

-Binding of Aminoacyl tRNA (escorted by elongation factor) to the A site
-GTP hydrolysis and release of elongation factor (EF-Tu or eEF1A)
-Peptide bond formation between aminoacyl in A site and P site
-Ribosome translocates, with deacylated tRNA in P site moving to the E site and releasing. Facilitated by EF-G or eEF2

292
Q

Describe the steps in the scanning process of translation

A

-Formation of preinitiation complex assembles, with EIF4F facilitating the binding to the cap
-This forms a 48S complex which scans for the start codon
-Once bound and stabilised, the large ribosomal subunit joins, forming the initiation complex

Year 2 Semester 1 (5 decks)

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