What happens to the siRNA strands after the siRNA molecule is incorporated into the RISC complex?

Question

BlackTom AI · Accepted Answer

RISC retains the siRNA guide strand, discarding the passenger strand so the guide can direct mRNA targeting.

1) Relevant knowledge points and concepts
- RNA interference (RNAi) uses short interfering RNAs (siRNAs, ~21–23 nt) processed by Dicer from long dsRNA.
- The siRNA duplex has two strands: the guide (antisense, complementary to target mRNA) and the passenger (sense).
- The RNA-induced silencing complex (RISC), containing Argonaute proteins, loads the duplex and selects one strand to remain as the active guide.
- Strand selection depends on thermodynamic asymmetry (the strand with a less stably paired 5' end is usually chosen as guide).
- The passenger strand is removed (cleaved by Ago2 or unwound) and degraded; the guide remains bound to Ago and directs cleavage or repression of complementary mRNA.

2) Step-by-step reasoning process
- Dicer generates an siRNA duplex with 3' overhangs.
- The duplex is loaded into the RISC-loading complex; Argonaute inspects the duplex ends.
- Based on thermodynamic cues, Argonaute retains the guide strand; the passenger strand is displaced.
- If Argonaute has slicer activity (Ago2), it can cleave the passenger strand; otherwise helicases/unwinding factors separate the strands.
- The freed passenger fragment is degraded by cellular nucleases.
- The guide strand–Argonaute complex base-pairs with target mRNA and mediates mRNA cleavage or translational repression.

3) Calculations
- No numerical calculations are required.

4) Why the correct answer is correct
- The accepted molecular mechanism of siRNA-mediated silencing explicitly states that only the guide strand is retained in RISC to provide sequence-specific targeting, while the passenger strand is discarded and degraded.

5) Why the other options are incorrect
- (a) Guide strand is not converted into DNA—reverse transcription is not part of RNAi.
- (b) siRNA strands do not become structural components of ribosomes.
- (d) Both strands are not immediately degraded; the guide strand is preserved for targeting while only the passenger is removed.

6) Conclusion
This explanation confirms answer c: "The passenger strand is discarded while the guide strand remains active in targeting mRNA."

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