Notesale: Turn your study into money

Document Preview

Extracts from the notes are below, to see the PDF you'll receive please use the links above

---

MicroRNAs and Cancer
Revision article: https://www
...
nlm
...
gov/pmc/articles/PMC4009396/

General Overview
1
...

2
...

3
...



-


Typically, it is believed that there is a unilateral pathway from DNA to mRNA, but
miRNAs seem to defy this pathway as they do not encode any protein but instead
modulate protein production by destabilising mRNA, or promoting protein
production
...
elegans:
1
...

elegans in 1993 in two separate labs in the USA
...

- You do not need to know have any prior information of the genes, but only look for
‘deformed worms’ and ask the question, ‘what was the gene that was mutated to
lead to this’
...
In the 90s, the general agreement was that a mutated gene would lead to the
formation of a mutant phenotype, however, this was not the case for the lin-4 gene,
because it encoded small regulatory RNAs rather than proteins
...


3
...

The problem was that the miRNAs were not interacting in a perfect way with their
targets but forming these imperfect interactions in ‘bulges’
...
This was discovered in the year 2000: Let-7 pre-miRNAs are encoded in genomes of
different species, ranging from the C
...

- Regulated downstream components like lin-4, but the major difference is that this
gene was encoded in many multicellular organisms
...


2
...

Summary:
1
...

2
...

3
...

4
...

5
...

6
...

7
...





MicroRNA Biogenesis and Molecular Functions







•









The Canonical Pathway:
1
...

- Always have a 5’ cap
...

- Sometimes the miRNA can sit within the exonic or intronic part
...


2
...

3
...

- These TFs are expressed in different tissues in a non-uniform manner, which means
that these miRNAs can be expressed in a diverse and refined pattern of expression
...
After the precursor is made, the stem-look-like element is excised from the
precursor by the enzyme called Drosha, which makes up the microprocessor
complex
...



-

Drosha introduces this hallmark – introducing 2nt ‘sticky end’
...
This is then exported out of the nucleus called export-5/RanGTP (which also exports
t-RNA)
...

- Once in the cytoplasm, a second RNA enzyme that complexes with other proteins is
called Dicer, which is a cytoplasmic RNAseIII-type endoribonuclease that cuts off
(“dices”) the loop from pre-miRNA (b) to form a short RNA duplex (c) with
3’protruding ends
...

o There are 4 distinct Ago homologs in vertebrates Ago1-Ago4 – paralogs
because they come from they are duplicated within the same organism
coming from the same ancestral gene
...


-

The other strand is called “passenger” strand is normally degraded (another
demonstration of how this process is very uneconomic)
...
These Ago within the RISC complex bind to the guide strand and guide it to its
complementary sequence in 3’UTR of a Mrna target
...


7
...

- In general, in animals the less than perfect pairing is common
...

- In human or mouse, only the Ago2 maintains this enzymatic activity
...


-




SiRNA are double-stranded, 21-22 nt long that function to cleave Mrna by acting as
gene silencing guardians in plants and animals that do not have antibody-or cellmediated immunity
...


8
...

- M-RNA sequences that productively base-pair with the miRNA ‘seed’ region occur
within week secondary structure and are often surrounded by As or Us
...




9
...

o Meaningful way for the cell to get rid of mRNAs that are not being used for
translation
...
However, there is one miRNA that does not require Dicer, in which case the final
cleavage is done by Ago2 – whereby the enzyme mistakes the passenger strand and
cuts it as if it were the Mrna target
...
This leads to the production of mature miRNA called mir-451 – termed the dicerindependent pathway
...
Similarly, there is a pathway that does not include drosha, whereby the miRNA is
encoded as part of the intron
...
These introns are usually branched out and spliced, and at the beginning of the end
of these introns is where the mirtron is produced – thus not requiring drosha –
termed the Drosha-independent pathway
...
miRNAs can play multiple roles in cells: promote cell differentiation or proliferation
...

- These cell cycle inhibitors, such as p21 (an inhibitor of CDK) and Lats, are inhibitors
thus promoting cell proliferation
...
miRNAs can contribute to cellular differentiation, particularly neuron development
in nematodes:
- the miRNA lsy-6 is under the control of the TF, die-1,
- in the left chemosensory neuron, would express die-1 and lsy-6
- The right one would express cog-1 and miRNA-273
- Lsy-6 antagonises cog-1 and mir-273 represses die-1 – thus controlling for the fates
of these neurons
...
There are two types of genes: oncogenic or tumour suppressive, and this is also
reflected in miRNA biology, not all of them but a majority of one
...
Therefore, these would be activated or repressed in much the same way as their
protein counterparts
...
Oncogenic miRNAs target tumour suppressive mRNA, and vice versa
...


4
...

- Overexpression of the miR-17-19b cluster together with c-Myc induces aggressive
lymphomas in mice – thus functioning of oncogenic miRs
...

- This miRNA normally functions to rescue the cells from dying (less apoptosis) thus
leading to more aggressive tumours forming
...
The miR-371-373 cluster is upregulated in human testicular tumours, and
antagonising LATS2
...

6
...

- Mutations in this family lead to upregulation of RAS and HMGA-type 2, leading to
stemness of cancer stem cells, increasing aggressiveness of tumours and
subsequently, metastasis, due to their inability to inhibit proto-oncogenes
...

7
...

8
...

- MiRNA expression is often generally repressed in tumours
...




---