10: Non-coding RNAs and Gene Regulation

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Questions and Answers

Which of the following best describes the primary function of non-coding RNAs?

  • To serve as direct templates for protein synthesis.
  • To provide structural support within the cell's nucleus.
  • To transport amino acids to the ribosome during translation.
  • To regulate gene expression and perform other functions as RNA molecules. (correct)

Which of the following is a characteristic feature of microRNA (miRNA) biogenesis?

  • miRNAs are processed from longer precursor mRNAs. (correct)
  • miRNAs are translated into functional proteins.
  • miRNAs are directly transcribed by RNA polymerase I.
  • miRNAs function exclusively within the cell nucleus.

What is the role of the Dicer enzyme in small RNA regulation?

  • It methylates DNA to regulate gene expression.
  • It degrades improperly folded proteins.
  • It synthesizes mRNA from a DNA template.
  • It processes double-stranded RNA into smaller fragments. (correct)

What is the primary function of PIWI-associated RNAs (piRNAs)?

<p>To defend the genome against transposons and maintain genome stability. (D)</p> Signup and view all the answers

How do microRNAs (miRNAs) typically regulate gene expression?

<p>By binding to mRNA and promoting its degradation or blocking translation. (A)</p> Signup and view all the answers

Which of the following is a key feature distinguishing siRNAs from miRNAs?

<p>siRNAs induce mRNA cleavage, while miRNAs mainly repress translation. (B)</p> Signup and view all the answers

Which protein family is most directly associated with loading mature miRNAs?

<p>Argonaute. (B)</p> Signup and view all the answers

What is a 'seed region' in the context of the miRNA targeting?

<p>A 6-8 nucleotide sequence in the miRNA that is critical for target recognition. (B)</p> Signup and view all the answers

Which of the following is a known mechanism of gene regulation by microRNAs (miRNAs)?

<p>Inducing mRNA degradation or translational repression. (A)</p> Signup and view all the answers

What role does the microprocessor complex play in microRNA (miRNA) biogenesis?

<p>It processes pri-miRNAs into precursor miRNAs (pre-miRNAs). (B)</p> Signup and view all the answers

If a researcher discovers a novel small RNA that associates with PIWI proteins, what type of RNA is it most likely to be?

<p>PIWI-associated RNA (piRNA). (D)</p> Signup and view all the answers

Which of the following is a characteristic of miRNA transcription?

<p>miRNA loci are often polycistronic, resulting in clusters of miRNAs. (A)</p> Signup and view all the answers

What is the role of Exportin 5 in microRNA (miRNA) processing?

<p>It transports pre-miRNAs from the nucleus to the cytoplasm. (C)</p> Signup and view all the answers

What structural feature is characteristic of precursor microRNAs (pre-miRNAs) processed by Dicer?

<p>A stem-loop structure. (A)</p> Signup and view all the answers

How does the thermodynamic stability at the 5' end of a miRNA duplex influence RISC assembly?

<p>Lower stability at the 5' end promotes guide strand loading into RISC. (A)</p> Signup and view all the answers

What is the general function of GW182 proteins in miRNA-mediated gene silencing?

<p>To tether the RISC to mRNA and promote translational repression and mRNA destabilization. (A)</p> Signup and view all the answers

In the context of miRNA-mediated gene silencing, what is the primary outcome of deadenylation?

<p>mRNA destabilization and subsequent decay. (C)</p> Signup and view all the answers

Which of the following is a characteristic of Processing bodies (p-bodies) in the context of miRNA function?

<p>They are cytoplasmic sites where mRNA degradation and silencing occur. (D)</p> Signup and view all the answers

How does extensive base-pairing between a miRNA and its mRNA target typically affect gene expression?

<p>It results in mRNA cleavage and degradation. (B)</p> Signup and view all the answers

Which of the following most accurately describes the role of Argonaute (AGO) proteins in RNA interference (RNAi)?

<p>They bind small RNAs and use them to target complementary mRNA sequences. (C)</p> Signup and view all the answers

What is the primary function of the Drosha enzyme in miRNA biogenesis?

<p>To cleave pri-miRNAs into pre-miRNAs. (A)</p> Signup and view all the answers

Which of the following is a key characteristic of long non-coding RNAs (lncRNAs)?

<p>They are involved in regulating gene expression via various mechanisms. (B)</p> Signup and view all the answers

Which of the following is a characteristic of piRNA's mechanism of action?

<p>piRNAs are involved in transcriptional or post-transcriptional repression of transposons. (C)</p> Signup and view all the answers

Which of the proteins is necessary for pri-miRNAs processing?

<p>Drosha. (A)</p> Signup and view all the answers

What role does the PAZ domain play in Argonaute proteins?

<p>It binds to the 3' end of the guide RNA. (B)</p> Signup and view all the answers

What event is usually triggered by base-pairing at nucleotides 10-11?

<p>A conformational change and slicing. (D)</p> Signup and view all the answers

Which of the following is a non-canonical pathway?

<p>Dicer-independent. (A)</p> Signup and view all the answers

What is the function of TUTase?

<p>Two-nucleotide long 3' overhang. (A)</p> Signup and view all the answers

What is the relationship between mRNA and regulation of growth and cancer?

<p>microRNAs can regulate mRNAs related to growth and differentiation as well as being involved in cancer. (A)</p> Signup and view all the answers

Which of the following statements best describes the involvement of miRNAs in cancer development?

<p>miRNAs can function as both oncogenes and tumor suppressors depending on their target mRNAs. (C)</p> Signup and view all the answers

Which processing enzyme is linked to both siRNA and miRNA?

<p>Dicer. (B)</p> Signup and view all the answers

Which answer aligns the specific microRNA with the mechanism?

<p>miR-17~92, oncogene/tumor suppressor gene. (C)</p> Signup and view all the answers

Which sequence is part of LIN-4?

<p>UUCCCUGAGACCUCAAGUG (B)</p> Signup and view all the answers

Which of the following is evidence of mRNA stability?

<p>All of the above. (D)</p> Signup and view all the answers

What is the impact of high magnesium for an Argonaute target?

<p>mRNA cleavage. (B)</p> Signup and view all the answers

Which of the following is true about microRNA targeting?

<p>3' UTR structure matters. (D)</p> Signup and view all the answers

What proteins interact directly and act downstream of AGOs?

<p>GW182. (C)</p> Signup and view all the answers

Under normal conditions, for an Argonaute target, what event occurs?

<p>mRNA deadenylation and destabilization. (C)</p> Signup and view all the answers

What is the typical length of a miRNA molecule?

<p>Approximately 22 nucleotides. (A)</p> Signup and view all the answers

Flashcards

Non-coding RNAs

mRNAs that do not code for proteins but instead perform functions as RNA molecules.

microRNAs and siRNA

Small RNAs derived from processing and cutting longer precursor mRNAs.

lncRNA

Long non-coding RNAs.

Circular RNAs

Circular RNAs.

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microRNA gene regulation

microRNA-mediated gene regulation.

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RNAi and chromatin

RNA interference and chromatin.

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PIWI proteins

The PIWI proteins.

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Microprocessor Complex

A complex that processes primary microRNAs into precursor microRNAs, essential for microRNA biogenesis.

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Drosha function

Processes pri-miRNAs into ~65 nucleotide stem-loop precursor miRNAs (pre-miRNAs).

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Dicer function

Processes pre-miRNAs into small RNA duplexes (~21-25 nt).

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TRBP

A cofactor which enhances processing efficiency and tunes length during pre-miRNA processing.

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Argonaute Structure

It is a multi-domain protein with specific interactions to guide RNA and target mRNA.

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RISC Assembly

Assembles to perform the primary function of deadenylation

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RISC loading (+ATP)

The loading of the miRNA duplex into an argonaute protein.

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RISC Unwinding (-ATP)

The unwinding of the guide and passenger strand.

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Extensive base-pairing

Where the target and mRNA base pair.

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GW182 proteins

GW182 protein directs proteins to mRNA.

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Inhibition of translation initiation

These processes prevent ribosome recruitment.

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Inhibition of translation elongation

These processes block ribosome progression.

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Processing Bodies

Sites for microRNA function.

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mRNA degradation

This activity causes transcript breakdown.

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The seed region

miRNA is also known to target here.

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miR-17~92 Targets

Targets E2F1, HBP1, CDKN1A, NCOA3, ERa, PTEN, MECP2, HOXA5, VPS4B, MYCN, RAB14, DPYSL2, TGFBR2, TSG101, ARHGAP12, BACE1

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miR-21 Targets

Targets are genes PDCD4, PTEN, RECK, PPARa, TIMP3, FasL, TGFBR2, SERINB5, CDK2AP1, ТРМ1

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miR-221/222 Targets

Targets CDKN1B, KIT, PPP2R2A, p27kip1, CDKN1C, ERa, KIT, DDIT4, BNIP3L, ZEB2, TBK1, CREBZF, MYBL1, DKK2

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let-7 Targets

NIRF, NF2, CASP3, TRIM71

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miR-15/16 Targets

Targets BACE1, DMTF1, C22orf5, BCL2, ARL2, CCNT2, TPPP3, VEGFA, RARS, FGF2, ZNF622, DNAJB4, PURA, SHOC2, LUZP1, FNDC3B, ITGA2, ATG9A, CA12, TMEM43, YIF1B, TMEM189, VTI1B, RTN4, TOMM34, NAA15,PNP, SRPR, IPO4, NAPg, PFAH1B2,

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miR-200 Targets

Targets ZEB1, CTNNB1, BAP1, GEMIN2, PTPRD, WDR37, KLF11, SEPT9, HOXB5, ERBB2IP.

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miR-34 Targets

Targets are genes SIRTI, BCL2, YY1, MYC, CDK6, CCND1, FOXP1, HNF4a, CDKN2C, ACSL4, LEF1, ACSL1, MTA2, AXL, LDHA, HDAC1, CD44, BCL2, E2F3

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Study Notes

Non-coding RNAs

  • mRNAs don't code for proteins, and instead function as RNA molecules
  • microRNAs and siRNA are short RNAs derived from processing and cutting of longer precursor mRNAs
  • Long non-coding RNAs are known as lncRNA
  • Circular RNAs exist
  • Piwi-associated RNAs are called piRNAs

Small RNAs in Gene Regulation

  • MicroRNA-mediated gene regulation exists
  • RNA interference (RNAi) and chromatin are part of gene regulation
  • PIWI proteins are involved

Small RNA Regulation

  • miRNA length is ~22 nucleotides
  • siRNA length is ~21 nucleotides
  • piRNA length is 24-30 nucleotides
  • Drosha and Dicer are processing enzymes for miRNA
  • Dicer is a processing enzyme for siRNA
  • Zucchini and unknown trimming enzymes are processing enzymes for piRNA
  • AGO is a subclade for miRNA
  • AGO is a subclade for siRNA
  • PIWI is a subclade for piRNA
  • miRNA's mechanism of action is translational repression and mRNA degradation
  • siRNA's mechanism of action is RNA cleavage
  • piRNA's mechanism of action is transcriptional or post-transcriptional repression of transposons, as well as multigenerational epigenetic phenomena in worms
  • miRNA function is regulation of protein-coding genes
  • siRNA function is regulation of protein-coding genes and transposons, and antiviral defense
  • piRNA function includes transposon silencing (pre-pachytene piRNA), unknown function (pachytene piRNA), and unknown function in soma (piRNA-like small RNA)

MicroRNA Transcription

  • Usually transcribed by RNA Pol II
  • Long (> 1 kb) highly structured primary microRNA (pri-miRNA) transcript can have a dual role as an mRNA
  • Introns of coding or non-coding transcripts and exonic regions are part of microRNA transcription
  • miRNA loci are often polycistronic, for example, miR-17-92 cluster
  • Some viral miRNAs are transcribed by RNA Pol II
  • Drosha is an RNase III-type endonuclease
  • Drosha processes pri-miRNAs into ~65 nt stem-loop precursor miRNAs (pre-miRNAs)
  • Pre-miRNAs have a 5' phosphate and 2 nt, 3' overhang
  • DGCR8 is an essential cofactor
  • Pre-miRNAs are exported to the cytoplasm by Exportin 5

Cytoplasmic pre-miRNA Processing

  • Dicer is an RNase III-type endonuclease
  • Dicer shows a preference for Drosha products that have a 2 nt and 3' overhang
  • Dicer processes pre-miRNAs into small RNA duplexes that are ~21-25 nt in length
  • Products also have a 5' phosphate and 2 nt, 3' overhang
  • TRBP is a cofactor that affects processing efficiency and tunes length
  • PACT is a cofactor with an unclear role

RNA-induced Silencing Complex

  • RISC assembly Involves loading (+ATP) of the miRNA duplex into an Ago protein
  • The complex unwinds (-ATP, using a 'rubber band' model)
  • The mature 'guide' miRNA is used vs. the passenger (*) strand
  • It depends on thermodynamic stability at the 5' end (preference for 5' U)
  • Mismatches in the miRNA duplex at 2-8 and 12-15 promote unwinding

Targetting via base-pairing interactions

  • Other important parameters for miRNA targeting include
    • 3' UTR structure
    • Distance from the ORF and/or the poly(A) tail
    • RBP sites in the 3' UTR
    • miRNA cooperation (~8-30 nts)
  • GW182 proteins are silencing effectors
  • They Interact directly with and act downstream of AGOs
  • Direct tethering of GW182 to mRNA leads to translational suppression and mRNA destabilization

###Targeting

  • Has been shown to have an effect on mRNA stability
  • Limited miRNA:mRNA base-pairing prevents 'slicing'
  • miRISC triggers rapid deadenylation of target mRNAs
  • This all goes through interactions with GW182 and the CCR4/NOT deadenylation complex (likely through CAF1)
  • mRNA can then be de-capped by DCP1/2 enzymes, which are activated by their cofactors
  • mRNA is then turned over by 'scavenging' nucleases (exosome and Xrn1/2)

MicroRNAs and Cancer

  • MicroRNAs can regulate mRNAs related to growth and differentiation
  • MicroRNAs can also be involved in cancer

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