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Molecules to Medicine I > Expression of Gene Control > Flashcards

Expression of Gene Control Flashcards

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1
Q

What are the eukaryotic DNA control elements?

A

TATA box
Promoter proximal elements
Enhancers

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2
Q

Describe the TATA box

A

25-35bp upstream of transcription start site
determines site of transcription initiation
Directs binding protein of RNA pol I (where general transcription factors bind)

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3
Q

Describe promoter proximal element

A

within 200bp upstream of transcription start site
~20bp long
regulates transcription -> bound by cell specific factors

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4
Q

Describe enhancers

A

Multiple control elements, 8-20 bp long each=> up to 100-200 bp long total

200 tens of kbp upstream or downstream from promotor, or last exon of gene, also within intron

Regulate transcription in cell specific way

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5
Q

Describe thalassemia β

A

inherited anemia caused by insufficient production of β-globin protein by erythroid cells

Caused by many mutations, including at promoter-> reduces amound of β-globin mRNA -> decreases protein production (clinically mild)

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6
Q

Describe thalassemia γδβ

A

caused by deletion of locus control region (LCR) of β-globin gene cluster
Hemophilia B Leyden

X linked clotting disorder
1% of normal factor IX until puberty in males (result of mutation in promoter => prevents binding of transcriptional activators )

After puberty up to 60% of normal factor IX due to androgen receptor activation that has overlapping binding sites at promoter

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7
Q

Describe fragile X syndrome

A

Mental retardation, dimorphic facial features, macroorchidism (abn large testes) in 1/1,500 males

CGG repeat at 5’ region of FMR I gene-> methylation of cytosine residues in CpG-> transcriptional inactivation of FMR I gene

Normal = 6-50 repeats, Fragile x = > 200 repeat -> increased transcriptional silencing

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8
Q

What is the role of transcriptional activators and repressors?

A

They are proteins that are encoded by one gene but act on other genes (Trans) regulating (increasing or decreasing) transcription

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9
Q

What are the 2 classes of sequence activators and repressors?

A

Sequence specific binding proteins

Cofactors

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10
Q

How do sequence specific binding proteins work?

A

Binds promoter or enhancer in target genes to reg. transcription

Usually binds element 6-8bp long

Bind by inserting α Helices into major groove of DNA -> creates contact between amino acid side chains of protein and based of DNA

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11
Q

How do cofactors work?

A

Do not bind DNA directly

bind sequence specific DNA binding proteins -> affect translation

Cause sequence specific DNA binding proteins to work more or less efficiently

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12
Q

What are the domains of sequence specific DNA binding proteins

A

They have 2 (modular)

DNA binding domain - reads DNA and binds with high specificity – highly conserved

Activation/ repressor domain - binds cofactors, on outside, bind general transcription factors, not highly conserved

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13
Q

Describe helix turn helix sequence specific DNA binding proteins

A 
Homeodomain 
act on simillar genes 
Important for development
HOX family, Pit 1, MSX
60 aa domain
 2 alpha helicies -> motif
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14
Q

Describe zinc finger sequence specific DNA binding proteins

A

tetrahedral organizaiton created by Zn residue

Bind nuclear receptors for Estrogen, androgen, retinoic acid

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15
Q

Describe the basic helix loop helix sequence specific DNA binding proteins

A

zipper with looped region
myoD, myogenin, Myf5
homo and hetero dimers

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16
Q

Describe the basic leucine zipper

A

dimerized through alpha-helical zipper domains
no loop
homo and heterodimerization
c-fos, c-jun

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17
Q

Describe androgen insensitivity syndrome

A

decreased androgen response due to mutation in AR DNA binding domain or ligand binding domain <- mutation in binding domain or ligand binding domain (zinc finger)

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18
Q

Describe waardenburg syndrome type II

A

Mutation of MITF gene renders it nonfunctional -> this affects transcription of genes important in pigmentation and hearing

protein made but does not function -> cannot bind to DNA to activate Genes (basic helix loop helix)

19
Q

Describe Msx2 and craniosynostosis

A

Proline to histidine substitution-> causes tighter binding to DNA -> excessive expression of gene-> premature fusion of skull

20
Q

How is combinatorial control a mechanism for controlling gene expression?

A

Increases number of potential sequences where family or sequence specific transcription factors can bind -> new DNA binding specificity

Available to zinc finger, bZIP, bHLH

21
Q

How do transcriptional activators and repressors control transcription once they are bound to DNA?

A

by regulating assembly of initiation complexes

regulating rate of initiation of transcription

regulating changes in chromatin structure (ability of transcription factors to bind promoters)

22
Q

What are the 2 classes of chromatin remodeling factors? How do they work?

A

DNA dependent ATP-ases

  • SWI/SNFs
  • disrupt histone octamers and DNA

HATs and HDAC
-reversibly modify histones via acetylation

23
Q

What are HATs and HDACs and how does their activity influence transcription?

A

HATs: histone acetyltransferases

  • Acetylate n-terminal of histone
  • Neutralizes positively charged ends -> decrease DNA interaction?
  • Acetylation of lysine -> specific transcription factor binding -> pattern of Acetylation = code to recruit factors & influence binding
  • Co-activators

HDACs: Histone deacyetylases

  • Keep, return + charge -> interaction with – DNA?
  • Acetylation of lysine (pattern) = code for transcription factor binding
  • Co-repressors

Trans acting factors can work as activators or repressors by recruiting HATs or HDACs

24
Q

Give an example of a disease where histone acytlation has been altered, describe the defect

A

Rubinstein-Taybi Syndrome

  • Rare 1/125,000
  • Growth retardation, mental retardation, craniofacial dysmorphism, abnormally broad thumbs and great toes
  • Mutation of CREB binding protein (CBP) -> co-activator of many transcription factors
  • Transcription of MANY genes does not take place or is insufficient

Leukemia

  • Hematopoietic malignancy
  • Gain of function of fusion-proteins -> altered activity of regulators
25
Q

How do activators/repressors modulate transcription?

A

interact with general transcription factors/ Pol II proteins

Change initiation or elongation of transcript
Influence rate of initiation

26
Q

How do activators/repressors modulate transcriptional machinery?

A

Influence rate of assembly

27
Q

How do activators/repressors modulate chromatin?

A

change transcription factor’s ability to bind (accessibility)

28
Q

How are transcriptional regulation and specificity achieved?

A

regulation
-depends on DNA-protein and protein-protein interaction-> change DNA conformation or chromatin structure and initiation complex forms

specificity
-depends on binding of transcriptional activators or repressors to DNA control elements

29
Q

How does protein-DNA interaction contribute to transcriptional control?

A

control is combinatorial
- several thousand transcriptional activators/repressors can differentially change expression of genes in different cells in response to different stimuli

30
Q

What is Euchromatin?

A

Where genes reside in accessible form of chromatin

31
Q

What is heterochromatin?

A

Repressed because DNA is inaccessible

-on centromeres, telomeres and internal chromosome positions

32
Q

What is the difference between constitutive and facultative heterochromatin?

A

Constitutive - always inaccessible, contains satellite DNA
ex. centromeric DNA

Facultative - can be euchromatin, depends on cell type, developmental stage and enriched LINE sequences
ex. X-inactivation

33
Q

How are sequence specific DNA binding proteins regulated?

A

regulation of conformation of DNA binding protein changes due to ligand binding (i.e. zinc finger)

Regulation of entry of DNA binding proteins into nucleus (nuclear localization region- NLR)

Regulation of amount of transcription factor in cell ([concentration])

Regulation of DNA binding

Phosphorylation of DNA binding protein changes protein degradation, recruitment of co-activators and DNA binding

34
Q

How is the activity of nuclear hormone receptors controlled?

A

In nuclear receptors binding of hormones affect receptor and recruitment of co-activators/ repressors and translocation into nuclies
i.e estrogen receptor activation, glucocorticoid receptor activation

35
Q

How does Tamoxifen act in breast cancer therapy?

A

Normal: estrogen induces transcriptional activation through estrogen receptor (causes Dimerization of ER -> histone acetylation-> pol II recruitment -> CTD Phosphorylation -> ER/p160 release)

In pathology (ER + breast cancer): Tamoxifen binds ER, prevents recruitment of HATs -> no acetylation of histones -> no recruitment of pol II (may recruit depressors)

36
Q

How does NFkb pathway work? What drug changes its pathway, and how does it work?

A

Held in cytoplasm by binding to inhibitor (IkB) which masks nuclear localization signal

  • If Ikb phosphorylated -> degraded -> NFkB released and moves to nucleus
  • In nucleus NFkB turns on genes involved in inflammatory response

Asprin is anti-inflammatory in part b/c inhibits phosphorylation -> IkB not degraded and NFkB cannot enter nucleus to activate inflammatory genes

37
Q

How does NF-AT pathway work? What drug changes this pathway and how does it work?

A
  • Phosphorylated in cytoplasm, cannot enter nucleus
  • High intracellular Ca -> activates calcineurin’s phosphatase activity -> NF-AT dephosphorylated -> nuclear localization sequence exposed -> goes to nucleus
  • In nucleus NF-AT affects transcription of immune response genes & heart function

Immunosuppresants (cyclosporine and FK506) -> inhibit calcineurin => inhibit NF-AT

38
Q

Describe the β-Catenin pathway and how it can be changed

A

Typically phosphorylated by APC, GSK3 and Axin (due to absence of Wnt signaling)
-if Wnt signaling occurs -> β-Catenin no longer phosphorylated (targeted for ubiquitination) b/c APC and complexing proteins destabilized -> cytoplasm concentration increases

  • up [β-Catenin] -> some enters nucleus -> interacts with TCF family transcription factors -> promotes expresson of Wnt responsive genes

Positive feedback loop

39
Q

What type of cancer is APC mutation involved in?

A

Colon cancer

40
Q

How does p53 work normally?

A

Guardian of Genome
active in growth arrest, DNA repair, apoptosis

down regulated by MDM2 binding (masks activation domain targets for destruction by ubiquitin- proteosome pathway

present in >50% of cancers

41
Q

Describe ubiquitin and its function

A

ubiquitous (highly conserved)
yeast = human

Covalently linked to protein by ATP dependent pathways of E1, E2 & E3 enzymes

Once ubiquinated, proteins taken to 26s proteosome for degradation

42
Q

Describe how DNA binding activity of sequence specific DNA binding protein can be inhibited

A

Id proteins
Heterodimerize with helix loop helix domains
-prevent DNA binding through loss of basic domain

43
Q

Describe a protein modification that can alter activity of a sequence specific DNA binding protein

A

Phosphorylation affects activity of trans acting factors

  • CREB (Cyclic AMP response element binding protein) -> phosphorylated due to events triggered by ligand binding to guanine nucleotide binding protein coupled receptor
  • CREB in active until phosphorylated -> if phosphorylated recruits histone acytly transferase, CBP (with HAT activity -> RNa pol II) => => activation of gene

Rubinstein-Taybi Syndrome

  • Rare 1/125,000
  • Growth retardation, mental retardation, craniofacial dysmorphism, abnormally broad thumbs and great toes
  • Mutation of CREB binding protein (CBP) -> co-activator of many transcription factors
  • Transcription of MANY genes does not take place or is insufficient
44
Q

Beyond transcriptional regulation, how can gene expression be controlled?

A

control of mRNA export from nucleus

control of mRNA degradation

control of efficiency of translation

control of protein degradation

Molecules to Medicine I (9 decks)

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