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CANCER BIOLOGY > LECTURE 3 (Regulation of gene expression) > Flashcards

LECTURE 3 (Regulation of gene expression) Flashcards

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1
Q

What is the main function of regulating gene expression?

A

Maintaining the functional integrity of the cell

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2
Q

What is cancer?

A

A disease of the genome at the cellular level that may be manifested by alterations in gene expression

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3
Q

What must happen to DNA to make it accessible to RNA Polymerase?

A

Eukaryotic DNA packaged in chromatin structures -> gene expression requires chromatin remodelling -> makes desired gene region accessible to RNA Polymerase and other proteins required for gene expression

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4
Q

Wha are the primary regulators of gene expression?

A

Transcription Factors

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5
Q

What is important about Transcription factors?

A
  • Can affect transcription directly by controlling function of RNA polymerase or indirectly by affecting chromatin structure
  • Contain at least 2 recognisable domains
    [DNA-BINDING DOMAIN and an ACTIVATION DOMAIN]
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6
Q

What are Transcription Factors?

A

Proteins that can bind specific DNA sequences and regulate gene expression

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7
Q

What are DNA binding motifs?

A

DNA binding proteins that make specific contacts to dsDNA molecule without breaking the hydrogen bonds -> Contacts occur between the DNA binding proteins and the edges of the base pairs that are exposed in the grooves of the DNA (especially MAJOR GROOVE)

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8
Q

Describe the Zinc finger motif

A
  • Domain is configured around a ZINC ATOM that links TWO CYSTEINES and TWO HISTIDINES
  • Consists of a simple ββα fold
  • Side chains of specific amino acids recognise a specific DNA sequence
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9
Q

What is the function of the Activation domain?

A
  • Bind to other transcription factors and co-regulators
  • Recruit chromatin-modifying proteins such as HISTONE ACETYLASES or DEACETYLASES
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10
Q

What is a Co-activator?

A

A type of transcriptional co-regulator that binds to a transcription factor to increase the rate of transcription of a gene or set of genes

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11
Q

Which coactivator is often over expressed in breast cancer?

A

The steroid receptor coactivator (SCR) NCOA3

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12
Q

What are the two main types of transcription factors?

A
  • General transcription factors
  • Sequence-specific transcription factors
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13
Q

What is the function of General transcription factors?

A

Interact with RNA Polymerase, forming the initiation complex required for the initiation of transcription

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14
Q

Which general transcription factors does RNA Polymerase II need?

A

TFIIA, B, D, E, F and H

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15
Q

What are sequence-specific transcription factors?

A

DNA-binding proteins that recognise specific nucleotide sequences and regulate gene expression

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16
Q

Describe the function of Sequence-specific transcription factors

A
  • Can act positively to promote TRANSCRIPTION or negatively to promote GENE SILENCING
  • In eukaryotic cells, RNA polymerase cannot recognise promoter sequences themselves -> task of gene-specific factors to create a local environment to attract general factors -> attract polymerase
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17
Q

What are Co-activators/Co-repressors?

A

Proteins that bind to the sequence-specific transcription factors and modulate their function by repressing or activating gene expression

18
Q

What are the major characteristics of Cyclic AMP response element binding protein 1 (CREB)?

A
  • General transcription factor
  • Expressed in all nucleated cells
  • Overexpressed in HEMATOPOIETIC and SOLID TUMOURS compared with control tissues -> identification of CREB associated cancers
19
Q

What is Activating Protein-1?

A

A transcription factor important for the processes of growth, differentiation and death playing a role in carcinogenesis

20
Q

What are the properties of Activating Protein-1?

A
  • Composed of two components and can be produced by dimers of proteins from the Jun and For families
  • Activated AP-1 can bind to a specific DNA sequence “5’-TGAG/CTCA-3’” which is located in the promoter and therefore regulates the transcription of downstream target genes
21
Q

Describe the regulation of gene expression by the oestrogen receptor and by small-molecule modulators of ER function

A

1) Oestrogen steroid hormone ESTRADIOL binds to the ligand binding domain (LBD) of the ER to induce a CONFORMATIONAL CHANGE -> facilitates co-activator recruitment and activation of gene expression
2) Binding of a selective oestrogen receptor modulator (SERM) to the LBD blocks co-activator recruitment -> blocks gene activation
3) Binding of a selective oestrogen receptor degrader (SERD) promotes PROTEASOME-MEDIATED DEGRADATION of the ER -> blocks gene activation

22
Q

Describe Chromatin structure

A
  • Human DNA present in nucleus of cells in the form of 46 chromosomes
  • Chromatin: a thread of DNA (60%), associated RNA (5%) and protein (35%)
  • Simplest organisation = beads on a string array
23
Q

What are Histones?

A

A group of basic protein that associate with DNA and help the DNA to condense into chromatin

24
Q

Describe the structure of histones

A

Large proportion of +ve charged amino acids (Lysine + Arginine) -> DNA is -ve charged due to phosphate groups on its backbone -> Strong attraction between opposite charges -> High affinity binding between histone and DNA -> Nucleosome

25
Q

Histone proteins are composed of which types?

A
  • Core histones (H2A, H2B, H3 and H4)
  • Linker histones (H1)
26
Q

What does the degree of compaction or relaxation of chromatin determine?

A

How readily the DNA in a portion of chromatin can be transcribed -> HIGHLY-COMPACT chromatin cannot be transcribed (transcriptionally “silent”) whereas RELAXED chromatin is accessible for transcription

27
Q

What is the difference between Acetylated and Deacetylated chromatin?

A

Acetylated chromatin = Open and transcriptionally active

Deacetylated chromatin = Compact and transcriptionally repressed

28
Q

Describe Acetylation of Histones

A
  • Histone Acetyl Transferases (HATs)
  • Adds acetyl groups to histone tails
  • Reduces +ve charge and weakens interaction of histones with DNA
  • ALLOWS TRANSCRIPTION
29
Q

Describe Deacetylation of Histones

A
  • Histone Deacetylases (HDACs)
  • Removes acetyl groups from histone tails
  • Increases interaction of DNA and histones
  • REPRESSES TRANSCRIPTION
30
Q

What are the potential treatments available for HDAC inhibitors?

A

Treatments for cancer through the ability to epigenetically restore normal expression of tumour suppressor genes which may result in cell cycle arrest, differentiation and apoptosis

31
Q

Name some HDAC inhibitor drugs

A
  • VORINOSTAT and ROMIDEPSIN = used in treatment of cutaneous T-cell lymphoma (a disorder in which malignant T cells form tumours in skin)
  • BELINOSTAT and ROMIDEPSIN = used in treatment of peripheral T-cell lymphoma (a disease in which malignant T cells are found in a variety of tissues)
  • PANOBINOSTAT with BORTEZOMIB and DEXAMETHASONE = treatment of multiple myeloma (lymphoma caused by abnormal B cells)
32
Q

What are the properties of methylation?

A
  • Methylation of cytosine bases by a DNA METHYLTRANSFERASE favours the incorporation of DNA into heterochromatin
  • DNA methylation occurs in the C of a 5’-CG-3’ sequence
  • Methylation within the promoter region correlates with TRANSCRIPTIONAL SILENCING -> important in carcinogenesis when critical genes involved in tumour suppression are switched off
33
Q

What is the importance of hypermethylation associated with the inactivation of BRCA1?

A

Hypermethylation is associated with the inactivation of BRCA1 in non-inherited breast cancer and therefore may be another way of accomplishing loss of function

34
Q

What is the function of DNMTs?

A

DNMTs catalyse DNA methylation -> alters patterns of gene regulation and expression -> affects chromosome stability, embryo development and cell differentiation

35
Q

DNA Methylation inhibitors have a class of cytidine analogues of which types?

A
  • NUCLEOTIDE ANALOGUE (DECITABINE and AZACITIDINE) bind to DNA to form a covalent complex that promotes the degradation of DNMT
  • NON-NUCLEOTIDE ANALOGUE (PROCAINAMIDE) which binds directly to methylated region of DNMT
36
Q

Which disorders are nucleotide analogue drugs approved to treat?

A
  • Acute myeloid leukaemia (AML)
  • Chronić myelomonocytic leukemia (CMML)
  • Myelodysplastic Syndromes (MDS)
37
Q

What are Telomeres?

A

Repetitive DNA sequences at the ends of all human chromosomes

38
Q

What are the properties of Telomeres

A
  • Several thousand repeats of TTAGGG
  • Protect chromosomes -> without them, ends of chromosomes would be “repaired” -> chromosome fusion and massive genomic stability
  • Separate one chromosome from another in DNA sequence
  • Regulates individual cell division
  • Telomeric sequences shorten each time the DNA replicates
39
Q

What is telomerase?

A

A ribonucleoprotein enzyme complex that has been referred to as a cellular immortalising enzyme

40
Q

What is the function of telomerase?

A
  • Stabilises telomere length by adding HEXAMERIC repeats onto telomeric ends of chromsomes
  • High telomerase activity exits in germ cells, stem cells, epidermal skin cells, follicular hair cell and cancer cells
41
Q

Which anti-telomerase drug has entered Phase II clinical trials?

A

Imetelstat

[effective against pediatric brain tumours]

CANCER BIOLOGY (7 decks)

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