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Developmental Genetics and Embryonal Cancers > miRNA and cancer > Flashcards

miRNA and cancer Flashcards

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1
Q

What enzyme was introduce into petunias that lead to the discovery of miRNAs

A

Charcone Synthase

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2
Q

What cuts pri-miRNA to pre-miRNA

A 
The microprocess (DROSHA+DGCR8)
Chops of the stem-loop
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3
Q

What cuts the pre-miRNA to miRNA

A

Dicer

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4
Q

Where do the majority of miRNA occur

A

40% occur in introns

Mainly occur in promoters

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5
Q

What are the methods of miRNA translation

A

1) Independent promoter
2) Intronic
3) Extronic

In intronic and extronic the miRNA volume produced is controlled by hte amount of RNA produced. The microprocessor excises the miRNA

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6
Q

What type of enzyme is DROSHA

A

RNAaseIII Enzyme

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7
Q

Describe the roles of Drosha and DGCR8

A

DGCR8 has two RNA-binding domain –> anchors the pri-miRNA before drosha cleavage
Drosha recognises the structure of pri-miRNA cleaves it 11 nucleotides from the ss-RNA:ds-RNA junction
Generates a pre-miRNA that is 65-70 nucleotides long

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8
Q

Describe the role of Dicer

A

Dicer has a blade and handle domain
PAZ bocket at the bottom of the handle binds the 3’ end of RNA and anchors it in
There are 2 nuclease domains in the blade which then cuts the dsDNA 22 nucleotides from the end leaving a 2 nucleotide overhand

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9
Q

What is the central component of the RISC

A

AGO2 part of the Argonaut family of proteins

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10
Q

How does the RISC work to cause mRNA cleavage/splicing

A

A paz domain in AGO2 binds the 3’ end of RNA. This guides the base pairs to target mRNA. the mmiRNA:MRNA binding proteins psoition the RNAase domain in the muddle of the guide RNA and cuts between the 10th and 11th nucletide

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11
Q

HOw does the RISC work to cause mRNA translation inhibiton

A

Interations between the miRNA and the 3’ UTR initiated by ‘seed residues’
Seed residues are typically 7 complimentary base pairs and binds between 2-8 bases of the miRNA –> can then mediate translation repression

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12
Q

What are the methods of translational repression once the miRNA is bound to RISC

A

1) Repression of initiation –> removal of cap, inhibit incorporation of 60S ribosomal subunit
2) Inhibit ribosomal elongation
3) May recuit RNA decapping and deadenylating enzymes

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13
Q

What regions to miRNAs like to bind to

A

AU-Rich regions

AREs are present in many mRNAs, particularly growth factors, cytokines and short lived mRNAs

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14
Q

What is DICER syndrome

A

Cuases predisposition to many cancers
E.g. cystic nephoroma
Mainly childhood cancers

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15
Q

What do mutations in DGCR8 produce

A

Di George Syndrome

Cardiac abnormalities
Abnormal facies
Thymic hypoplasia
Cleft palate, cellular immune deficiency
Hypoparathyroidism with hypoalcaemia
22 --> 22q11 deletion
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16
Q

What gene can drive the expression of mirR17-92 cluster

A

MYC

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17
Q

What cancers in miR17-92 often overexpressed in

A

B Cell lymphomas e.g. Burkitts

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18
Q

What deletions often occur in CLL

A

miR15 and miR16

19
Q

What in frequently downregulated in lung cancer and neuroblastoma

A

let-7

20
Q

What are the two types of miRNAs we can use for therapy and what is the difference between them

A

shRNA –> hairpn RNA which needs dicer cleavage

siRNA –> no need for DICER cleaveage however needs complete complimentarity to prevent offtarget effects

21
Q

What ways can we influence miRNA expression

A

Upregulate using mimics

DOwn regulate using sponges

22
Q

What are the 2 different methods of delivering RNA for therapeutic usage

A

Transfection (siRNA/mimics)

Transduction (shRNA/miRNA)

23
Q

Example of miRNA used to treat liver cancer

A

AAV-mi-miR26

Targets cyclins D2 and E2 to cause cell cycle arrest and caused apoptosis in cancer cells

24
Q

What other miRNA has been used to treat liver cancer and liver mets

A

MiR34 –> targers CDK4

25
Q

What is the lipid nanoparticle containing 2 miRNAs

A

ALN-VSP
Targets VSF and kinesin spindle protein –> decreases tumour vascularisation and causes mitosis inhibiton
Well tolerated and decreased mets in patients

26
Q

What miRNA are frequently lost in CLL

A

miR15 and miR16 –> may be an early even an initiating mutation

27
Q

How does let-7 work

A

Negatively regulates Ras

28
Q

What do miR15/16

A

Target bcl2

29
Q

How many miRNAs are in the miR17-92 cluster

A

at least 6

30
Q

What cancers is miR17-92 upregualted in

A

Breast and prostate

Promotes proliferation, angiogeneisis and cooperates with myc

31
Q

What oncogene activates the miR17-92 cluster

A

Myc –> it is an important cluster to upregualte for B cell proliferation –> however overexpression can lead to lymphoproliferative disorders

32
Q

What miRNA is often increased in mice B cells lymphomas

A

MiR155 –> the overexpression of this single miRNA can lead to tumours

33
Q

What miRNA does p53 induce

A

miR34a

34
Q

Dysregulation of what miRNas can affect the ERalpha receptor

A

dysregulation of miR221/22 can slilence the recepot and inhibit TSGs, this may contribute to the aggressiveness of breast cancers that are oestrogen receptor negative

35
Q

In AML what miRNA can be dysregulated

A

In AML: decreased ALL and DNMT3a expression
But increased p16 expression
Hence the potential to treat cancer with miRNAs

36
Q

What organs have good uptake of miRNAs

A

liver, spleen, bone marrow, kidneys@

37
Q

Give an example of where complimentary miRNAs doesnt always lead to mRNA degradation

A

In Plants: miR172- AP2 protein –> has complete complimentarity but doesnt lead to miRNA degradation

38
Q

what miRNAs is important for neuronal diversity

A

Lys6 –> helps control L/R assymmetery

39
Q

What miRNA is important for directing B cell lineages

A

miR181

40
Q

What group of genes are closely related to miRNAs

A

Hox genes

41
Q

What are the two miRNAs that are embedded within hox genes

A

miR10 - Hoxb4 –> similar expression paterns

miR116 - Hoxb8 –> have inverse expression as miR116 has near perfect complimetarity to the 3” UTR of Hoxb8 mRNA

42
Q

how are miRNAs exported from the nucleus to the cytoplasm

A

Exportin5 transports it in a Ran-GTP dependent manner

43
Q

How does DCGR8 interact with Drosha

A

DCGR8 has a NH-2 terminal WW domain –> which can interact with the proline rich NH2 terminal of Drosha

44
Q

What is monoallelicly delted in DiGeorge syndrome

A

DGCR8 in 90% of cases

Developmental Genetics and Embryonal Cancers (18 decks)

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