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Basic Principles Of Medicine 1-FTM 1 > Post Transcriptional Modification > Flashcards

Post Transcriptional Modification Flashcards

1
Q

Where do UTR(untranslated leader sequence) occur?

A

UTRs occur in the mRNA from the transcription initiation to the translation start site (5’ UTR) and the transcription terminator (3’ UTR) during transcription

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2
Q

Briefly compare mRNA structure: prokaryotes and eukaryotes

A

The 5’ and 3’ end of bacterial mRNA are unmodified
-Prokaryotic mRNA may be polycistronic

  • Eukaryotic mRNA contains modification:
    • 7-methylguanosine cap on the 5’ end
    • Poly-adenylation at the 3’ end
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3
Q

Summarize the editing of mRNA in eukaryotes undergo before becoming mature mRNA

A
  • Modification of the 5’ end of the mRNA
  • Polyadenylation of the 3’ end of the mRNA
  • Splicing of exons and the removal of introns
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4
Q

RNA polymerase II carries a set of pre-mRNA processing proteins on its c-terminal. Summarize the functions of these?

A

Shortly after the initiation of transcription, proteins are transferred to the nascent RNA (new,y formed RNA)

- capping factors
- splicing factors
- Polyadenylation factors

This transfer of RNA processing proteins begins after approximately 25 nucleotides of the mRNA are produced

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5
Q

Explain the capping of 5’ end of nascent mRNA

A
  1. Phosphatase: removes one phosphate from the 5’ end of the RNA
  2. Guanylyl transferase: adds a GMP in a reverse linkage (5’ to 5’ instead of 5’ to 3’)
  3. Guanine-7-methyl transferase: adds a methyl group to the 7 position of the terminal guanine
  4. 2’-O-methyl transferase: adds a methyl group to the 2’-O position to the next to last base on the 5’ end
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6
Q

Is the 5’ -methyl cap is specific ?

A

It is specific for eukaryotic mRNA and helps cell to distinguish between different RNA in the cell
- mRNA vs tRNA vs rRNA

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7
Q

What are the 5’-methyl cap important roles?

A

5’-methyl cap has important roles in the regulation of mRNA:

  • processing
  • transport
  • translation
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8
Q

What are the functions of 5’ mRNA capping?

A
  1. Regulates export of mRNA out of the nucleus
    - mRNA is exported in complexes that contain a Cap Binding Complex (CBC) at the end & RNA binding proteins along the rest of the sequence
  2. Required for the efficient translation of the mRNA into protein
    • The CBC is replaced by the translation factors elF-RE & elF-4G which facilitates binding of mRNA to the ribosome .
  3. Prevents 5’ degradation
    • The CBC & elF-4E/ elF-4G block the access of decapping enzymes to the cap. This increases the T1/2 of the mRNA (the life time of the transcript in the cytosol)
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9
Q

Summarize cleavage of 3’ mRNA Processing in eukaryotes

A

The modification of the 3’ end of the RNA is accomplished by several enzymes associated with RNA polymerase II that bind to specific sequences on the RNA:

  1. Cleavage and polyadenylation specificity factor (CPSF) binds to the hexa ear AAUAAA (Polyadenylation signal)
  2. Cleavage stimulating factor F (CstF) binds the GU- rich element beyond the cleavage site
  3. Cleavage factors bind to the CA sequence at the cleavage site
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10
Q

Summarize Polyadenylation to the 3’ end in eukaryotic mRNA

A
  1. Poly-A-polymerase (PAP) adds approximately 200A nucleotides to 3’ end produced by the cleavage
  2. Poly-A binding Proteins(PABP) binds to the Poly-A tail and assist in directing translation by the ribosome
  3. The cleaved fragment of the RNA is degraded in the nucleus
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11
Q

What are the functions of 3’ mRNA Polyadenylation?

A
  • Increased the T1/2 of the mRNA by protecting it from enzymatic degradation in the cytoplasm
  • Poly(A)-binding protein (PABP) binds to poly (A) tracts protecting mRNAs from ribonuclease attack
  • PABP interacts with e-IF 4G, and this interaction is thought to lead to the stimulation of translation of eukaryotic mRNAs
  • Aids in transcription termination I.e., facilitates transcription termination
  • Aids in export of the mRNA from the nucleus
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12
Q

How long are introns?

A

10 to over 100,000 nucleotides

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13
Q

Both _______ and ______ are transcribed to mRNA.

Intronic sequences are then removed by ______

A

Exons

Introns

Splicing

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14
Q

Where does splicing occur?

A

Splicing takes place at splice junctions located at the 5’ and 3’ end of the intron

  • The junctions have conserved consensus sequences (6-8 NT)
  • The 5’ end of the intron consensus sequence is always GU
  • The 3’ end of the intron consensus sequence is always AG
  • The branch site is always ‘A’ which is found 18-38 NT upstream from the 3’ end of the intron
  • Each splicing event removes 1 intron
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15
Q

What are the details of intron removal from a pre-mRNA molecule ?

A

5 small nuclear ribonucleoprotein particles (ssRNP) and numerous other splicing factors mediate splicing

  • The snRNPs are U1, U2, U4, U5 and U6 which form base pairs with consensus sequences at each end of the intron (intron-exon junctions)
  • After the 5 snRNPs bind the primary transcript, U1 and U4 leave, thus activating the splicesome
  • U2, U5 and U6 interact to bring neighboring exons into correct alignment allowing for two TRANS-ESTERIFICATION REACTIONS to occur
  • The 2-OH of the branch site A attacks they 5’ phosphate (p) at the splice donor site (5’ end of the intron) forming an 2’—> 5’ unusual phosphodiester bond
  • This reaction produces a lariat structure
  • This reaction also leaves a free 3’ hydroxyl at the end of exon 1 which will participate in the next reaction
  • The newly freed 3’-OH exon 1 then attacks the 5’ phosphate(p) at the splice-acceptor site to form a phosphodiester bond that joins exons 1 and 2
  • The excised intron is released as a lariat which is typically degraded
  • the mature messenger RNA molecules pass into the cytosol through pores in the nuclear membrane
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16
Q

What is systemic lupus Erythematosus?

A

An autoimmune disease with multiple symptoms including extreme fatigue, arthritis, fever, skin rashes and kidney problems

Individuals with this condition possess antibodies at react against their own nuclear proteins such as the U1 RNA component of the splicesome , histones, and topoisomerases

17
Q

How can molecular/biological diversity be increased in mRNAs and proteins?

A

By carrying out:

  • alternative splicing and/
  • RNA editing

Allows number of different proteins to be produced from the same gene

  • tissue specific isoforms
  • membrane bound or soluble isoforms
  • alternative intracellular localization
  • altered function
18
Q

What is alternative splicing?

A

RNA can be spliced in different ways to produce different species of mRNA in a process called alternative splicing

  • alternative RNA splicing can produce different forms of a protein from the same gene
  • about 60% of human genes are spliced in alternative ways producing a different set of mRNAs
19
Q

What is a-tropomyosin?

A

A protein with many isoforms: from regulating actin filaments in muscle cells (muscle contraction) and non-muscle cells(cell division and shape) membrane such as brain mRNA, fibroblast mRNA, smooth muscle mRNA, and striated muscle mRNA

20
Q

Summarize the control of alternative splicing

A
  1. Alternative splicing can occur due to intron sequence ambiguity. This may be due to ‘weak’ splice site sequences and therefore splicing choice occurs.
  2. Alternative splicing can also be directed by negative and positive control via proteins that blind to splice sequences and either repress or activate splicing at the site
21
Q

What are the conserved regions for RNA splicing?

A

Donor or and acceptor site

22
Q

What is B-thalassemia?

A

Many individuals with B-thalassemia hav mutations in the B-globin gene that generate additional splice sites within the mRNA, two examples shown

Example B shows a mutation in a normal accept is in intron 1 so that exon 2 is skipped

Example C shows a mutation in e normal acceptor site of intron 2 but there is a sequence upstream which I a weak acceptor site which is now used:
‘Activator of a ‘cryptic splice site’

23
Q

How can Limb Girdle Muscular Dystrophy be caused by mutations?

A
  • Some patients with Limb Girdle Muscular Dystrophy possess a mutation in the calpain-3 gene that generates a née splice site within exon 16
  • This results in a shorter calpain-3 mRNA that is missing many base pairs in exon 16
  • Mutation interrupts a codon causing downstream codons to be out of frame and thus producing a defective protein
24
Q

What is RNA editing?

A

Chemical modification of mRNA is known as RNA editing used by humans and many other species

25
Q

Summarize RNA editing by chemical modification of mRNA

A
  1. Chemical modification of mRNA
  2. Coding properties of transcript are altered
  3. Results in alteration in the amino acid sequence of the specified protein & generation of functionally different proteins

There are two types of editing:

  • Adenosine to Inosine (A-I)
  • Cytidine to Urdidine (C-U)
26
Q

How is RNA editing revealed?

A

RNA editing is a process in which information changes at the level of mRNA

-It is revealed by situations in which the coding sequence in an RNA differs from the sequence of DNA from which it was transcribed

In mammalian cells there are cases in which a substitution occurs in an individual base in mRNA, causing a change in the sequence of the protein that is coded

27
Q

How is RNA editing done in the liver/intestine?

A

In mammals, the apo-B gene encodes two alternative forms of the apolipoprotein B: Apo-B100(liver) and Apo-B48(intestine)

In the intestine, the apo-B mRNA is edited so that a premature stop codon is produced (CAA—> UAA) leading to the synthesis of the shorter Apo-48

This editing is accomplished by a cytidine deaminase enzyme

This is C-U editing in apolipoprotein B mRNA by cytidine deaminase

28
Q

Explain A-I editing: glutamate receptor mRNA in Brain

A

Editing of the glutamate receptor involves a single base change from A to I (inosine). This editing results in a codon change within mRNA from glutamine to arginine.

This editing affects an amino acid located in the nine wall of the ion channel and alters Ca2+ permeability.

This editing is a requirement for proper brain development
This editing is accomplished by the enzyme adenosine deaminase

29
Q

Do prokaryotes process mRNA?

A

No

30
Q

How does pre-mRNA become mature mRNA?

A

It’s spliced to remove introns with the aid of the splicesome -forms mature mRNA

31
Q

Which is the more common method of increasing diversity of mRNA?

A

Alternative slicing is more common than RNA editing

Basic Principles Of Medicine 1-FTM 1 (39 decks)

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