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BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies > Genetics and Epigenetics 2 - F Siebzenrubl > Flashcards

Genetics and Epigenetics 2 - F Siebzenrubl Flashcards

1
Q

What is DNA methylation?

1 mark

A

Addition of methyl group by DNMT1 onto cysteine residues

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2
Q

How are proteins recruited to DNA?

1 mark

A

Enzymes bound to methylated regions of DNA that lead to silencing of gene expression

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3
Q

What is the name of chromatin of a densley packed chromatin?

1 mark

A

Heterochromatin

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4
Q

What is loosely packed chromatin called?

1 mark

A

Euchromatin - DNA able to get access to TF associated with gene expression

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5
Q

What is a histone octomer and what does it do?

3 marks

A
  • Has 8 subunits and forms core histone (e.g. H1A and H2A)
  • Proteins attracts DNA to form structure
  • Tails of histones stick outside for DNA - important for DNA to modify
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6
Q

What are different post-translational modifications?

5 marks

A
  • Methylation
  • Phosphorylation
  • Sumoylation
  • Acetylation
  • Ubiquitylation
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7
Q

What modifications are catalyzed by enzymes?

3 marks

A

Acetyltransferases

Methyltransferases

Tyrosine kinases

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8
Q

How could the difference in positions of lysines affect DNA?

1 mark

A
  • Lysine methylated further up the histone could cause heterochromatin while further down makes euchromatin e.g. outside at H4
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9
Q

What is meant by the term ‘repressed state?

1 mark

A

Triple methylated lysine which will show repressed protein

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10
Q

What is poised chromatin?

1 mark

A

Contains both active and repressive transcription

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11
Q

What are the reader enzymes that interpret histone complexes?

1 mark

A
  • Polycomb (PcG) complexes - repressive
  • Trithorax (TrxG) complexes - activating
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12
Q

What does PRC2 do?

3 mark

A
  • Recognises methylated DNA binds to it and can catalyse methylation of lysine 27 on histone 3 H3
  • Also binds first to CpG islands ans recruits complexes that are mutually exclusive
  • Modulates gene expression by outcompeting complexes with other proteins associated with gene expression
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13
Q

What does PRC1 do?

A

Recognises methylated lysine 27 which catalyses ubiquitylation of different lysines leading to compaction and silencing of gene expression

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14
Q

What are the epigenetic mutations that occur in paediatric brain tumours glioblastomas?

4 marks

A
  • Mutations in lysine 27 - enzymes recognise it and modify it
  • PCR2 can’t bind to areas of chromatin lysine isn’t methylated so not recognised
  • Cause dysfuctional silencing - if gene there is GF causes unregulated growth
  • Oncogenes expressed where they shouldn’t be and TS not expressed - therefore get tumourogenesis
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15
Q

What are non-coding RNAs?

2 marks

A
  • RNA not associated with transcripted not turned into proteins
  • Short and long ones - can be epigenticallt regulated e.g. Xist - NCRs and silences copy of X chromosome
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16
Q

What does pri-mRNA mean?

1 mark

A

Primary mRNA

17
Q

How was junk DNA discovered?

3 marks

A
  • Injected RNA matching certain gene into worm
  • RNA had either same or similar sequence or had double stranded RNA (antisense RNA)
  • Found effect in offspring hertiable - inject double stranded RNA observe twitch phenotype - only double stranded RNA had an effect
18
Q

What does double stranded DNA do?

3 marks

A
  • Incorporated into RNA complex
  • Retains complementary strand and if binds, binds to mRNA sequence
  • Corresponding RNA degraded - post transcriptional way of silencing gene expression
19
Q

How is miRNA biogenesis initated?

A

Transcription miRNA biosynthesis starts with transcription pri-mRNA which is dyresgulated in most cancers

20
Q

What is the miRNA biosynthesis pathway?

5 marks

A
  • Conserved synthetic pathway for microRNAs - cells endogenous way of gene silencing
  • Expressed in gene, processed by Drosha complex into pre-mRNA and cleaves 5’ to 3’ end has stem loop structure
  • ^^ exported out the nucleus and incorporated into Dicer complex
  • Dicer generates mature miRNA which gets transported by organelle complexes into RNA induced signalling complex
  • Final piece of miRNA recognises RNA in cell by binding to complemetary sequnce - RNA gets ultimately degraded and can’t be expressed
21
Q

What does loq DROSHA/ DICER levels tend to indicate?

2 marks

(1 mark awarded for reference)

A
  • Advanced tumour stage and low clinical outcomes

Lin and Gregory, 2015

22
Q

What does miR-34 a,b and c do?

2 marks

(1 for reference)

A
  • Repress growth promoting genes and co-ordinate with other members of p53 TS network to inhibit uncontrolled cell proliferation and promote apoptosis

Lin and Gregory, 2015

23
Q

What are TS miRNAs?

1 mark

A
  • Silence oncogenes e.g. miR-200 families silence EMT - TFs e.g. Zeb1/2 which are important for stemness
24
Q

What do Zeb1/2 do?

4 marks

A
  • TS which regualate pathways of invasion, and resistance to therapy that’s upregulated in lots cancer
  • Therefore, mi-200 needs to be downregulated in cancer
  • Loss mi-200 expression - have increase in zeb1/2 expression which upregulate genes needed for tumour invasion
  • Zeb1/2 bind to miR-200 promoter to suppress transcrition of miR-200 - neg. feedback loop
25
Q

What are oncogenic miRNAs?

2 marks

A

Silence TS e.g. miR-222/221 family, and silence PTEN - if lost Ras pathway accelerates

26
Q

What is MYC?

4 marks

(1 for reference)

A
  • Oncoprotein that activates the expression of miR-17-93 cluster
  • Promotes cancer progession by controlling expression f E2F1
  • Thrombospondin 1 (THSB1) and connective tissue GF and other mRNAs to regulate cell progression and angiogenesis

Lin and Gregory (2015)

27
Q

What are HDAC inhibitors?

1 mark

A
  • Target histone deacetylases - inhibition causes increased acetylation
28
Q

What happens to cancer cells in the presence of HDAC inhibitors?

5 marks

A
  • Cancer cells can’t cope with increased acetylation so get increase in apoptosis
  • Irreversible change in DNA methylation means can’t be degraded and trigger degradation of methyltransferases
  • Delayed effect in 5-azacytine incorporated in cell
  • Once there, more cells proliferate an intgerated in DNA
  • DNA can’t be methylated anymore so get apoptosis in tumour cell
29
Q

Give an overview of miRNA biogenesis pathway.

6 marks

(1 for reference)

A
  1. miRNA genes trasncribed as pri-mRNAs by RNA polymerase II (PolII) in nucleus
  2. Long pri-mRNAs cleaved by microporcesses including DROSHA , DGCR8 - produce 60-70 nucleotide pre-miRNAs
  3. pre-miRNAs exported from nucleus, processed by XP05, further processed by DICER1 - a ribonucleaseIII enzyme produces mature miRNAs
  4. 1 strand mature miRNA loaded inot RNA-induced signalling complex (miRSC) which contains DICER1 and DO proteins
  5. This direct miRSC to target mRNAs by sequence complementary binding and mediate ene suppression by targetd mRNA degradation and translational repressoin processing bodies

(Lin and Gregory, 2015)

30
Q

How can DNA methylation and histone deacteylation cause miRNAs to act as tumour suppressors?

3 marks

(1 for reference)

A
  • miR-127 embedded in CpG islands and is upregulated (after simultaneous treatment with DNA methylation and histone acetylation inhibitors)
  • Slows down regulation of proto-oncogene BCL6

Peng and Cruce, 2016

BI3352: Cancer - Cellular and Molecular Mechanisms and Therapies (7 decks)

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