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In The Name Of God

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RNA editing

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Outline:1.RNA editing

2.RNA editing mechanisms

2.1 Editing by deamination

2.2 ADARs

2.3 Examples of A-to-I editing

2.4 Effects of RNA editing by ADARs enzyme

2.5 APOBECs

2.6 Examples of C-to-U editing

2.7 Effects of RNA editing by APOBECs enzyme

2.8 Insertion/Deletion Editing

3.Significance of RNA editing

4.Nervous system and RNA editing

5.Immune system and RNA editing

6.RNA editing and cancers

6.1 RNA editing and cancers: examples

7.Therapeutic intervention

8.Reference

4 1. RNA editing

Definition: Any process, other than splicing, that

results in a change in the sequence of an RNA

transcript

Relatively rare

Discovered in trypanosome mitochondria

Also occurs in a few chloroplast genes of plants, and at

least a few nuclear genes in mammals.

5 2. RNA editing mechanisms

Substitution Editing

Cytidine deaminases

Adenosine deaminases

Insertion/Deletion Editing

6 2.1 Editing by deamination

ADARs APOBECs

72.2 ADARs

Adenosine Deaminases Acting on RNA Binds to double stranded RNA

Convert adenosine to inosine (A-to-I),which the

ribosome translates as a G. Thus a CAG codon (for Gln)

can be converted to a CGG codon (for Arg).

8 2.3. Examples of A-to-I editing

92.4. Effects of RNA editing by ADARs enzyme

10 2.5. APOBECs

Apolipoprotein B mRNA editing Complexes Converts cytosine to uracil (C-to-U)

in RNAsingle-stranded DNA

11 2.6. Examples of C-to-U editing

Apolipoprotein B gene (in humans).

Apo B100 is expressed in the liver

Apo B48 is expressed in the intestines.

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2.7. Effects of RNA editing by APOBECs enzyme

13 2.8.Insertion/Deletion Editing

Requires a special class of RNA called guide RNA

(gRNA)

Multiple U’s are inserted into specific region of mRNAs

after transcription (or U’s may be deleted).

Found in the mitochondria of trypanosomes

Has also been found occur with

RNA transcripts in the mitochondria of the slime

mold Physarum polycephalum.

In measles virus transcripts

142.8.Insertion/Deletion Editing(…)

15 3. Significance of RNA editing

It is essential in regulating gene expression of

organisms.

RNA editing mutant was reported with strong defects

in organelle development.

Deficiency diseases(mostly cancers)

It is a mechanism to increase the number of different

proteins available without the need to increase the

number of genes in the genome.

May help protect the genome against some viruses

16 4. Nervous system and RNA editing

ADARs-mediated RNA editing

In both coding and noncoding transcriptomes

Editing in non-coding regions (such as microRNA

and 3´ UTR) is more frequent than in coding

regions

It is important for avoiding neurological diseases

175. Immune system and RNA editing

The replication of hepatitis delta virus (HDV).

ADAR1-S and ADAR1-L are involved in HDV editing

ADAR1-S functions in unstimulated cells

ADAR1-L functions in IFN-alpha-stimulated cells

APOBEC3 proteins play a vital role in innate defense

against mobile genetic elements such as viruses

For example, APOBEC3G has antiviral properties

(inactivate the HIV)

18 6. RNA editing and cancers

A-to-I editing is involved in human embryogenesis

This was found by studying the differentiation status

of pluripotent human embryonic stem cells

RNA regulation can modulate the expression of

oncogenes or tumor suppressor genes

So A-to-I editing may contribute to cancer

development and progression

19 6.1.RNA editing and cancers: examples

ADAR1 down regulation leads to regression of

established Chronic Myelogenous Leukemia in mice.

Down regulation of ADAR2 inhibited cellular

proliferation of pediatric astrocytoma and glioblastoma.

ADAR3 mRNA was decreased in glioblastoma

multiform (a brain tumor).

206.1.RNA editing and cancers: examples(…)

AB

C

21 6.1.RNA editing and cancers: more examples

ADARs

APOBECs

Brain

Bladder

Leukemia

Liver

Breast

General

Reduced editing of GluR in malignant gliomas

Reduced editing levels in tumors

Disease-associated alternative splicing of PTPN6 caused by RNA hyper-editing

APOBEC1-mediated editing of NAT1 mRNA in liver tumors

APOBEC3B upregulated in breast cancer cell lines

APOBEC signatures are observed in multiple cancer types

22 7. Therapeutic intervention

RNA editing has been suggested to be a therapeutic

target for CNS disorders

For example, RNA editing of the 5HT2C receptor may

affect cell signaling, drug response, and brain function.

A-to-I editing can also modulate the drug response of

some channels, such as Kv1.1 channel

Drugs for inhibiting RNA editing enzymes

23 7. Therapeutic intervention(…)

Editing enzyme levels could be used as prognostic

markers for early detection of cancer and to determine

post-therapeutic outcomes.

Elevated APOBEC3B levels would potentially represent a

promising biomarker for certain cancers like breast

cancer

low levels of ADAR1 have been associated with high risk

of childhood lymphoma

24 8.Reference

The emerging role of RNA and DNA editing in cancer

Review Article

Biochimica et Biophysica Acta (BBA) – Review on Cancer, Volume 1845, Issue 2, April 2014, Pages 308-316

Lotta Avesson, Guy Barry RNA editing and drug discovery for cancer therapy.

Huang WH, Tseng CN, Tang JY, Yang CH, Liang SS, Chang HW.

Scientific World Journal. 2013 Apr 24;2013:804505. doi: 10.1155/2013/804505. Print 2013. Review.

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