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Understanding RNA Interference: The Roles of Lin-4 and Let-7 in Gene Silencing

This document discusses RNA interference (RNAi), a process of post-transcriptional gene silencing where double-stranded RNA (dsRNA) induces degradation of homologous mRNAs, effectively reducing gene activity. The focus is on microRNAs (miRNAs) like Lin-4 and Let-7, which are small, non-coding RNAs that negatively regulate gene expression. It explores their biogenesis through the Dicer enzyme and their mechanisms of action in various organisms, highlighting their importance in gene regulation and potential implications in fields like cancer research.

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Understanding RNA Interference: The Roles of Lin-4 and Let-7 in Gene Silencing

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  1. Drosha 2002.09.17

  2. 121th Lab meeting 석사 2년 박 은 실

  3. Lin-4, Let-7

  4. What is RNAi ? A form of posttranscriptional gene silencing, in which dsRNA induces degradation of the homologous mRNA, mimicking the effect of the reduction, or loss, of gene activity. Kim VN., J Korean Med Sci . 2003

  5. MicroRNA • Small, Non coding RNAs • 21~25nt long • Negatively regulate gene expression • Lin-4, Let-7 • RNAse Ⅲ type enzyme Kim VN., J Korean Med Sci . 2003

  6. Examples of Metazoan miRNAs stem loops involving the mature miRNAs (red) The miRNAs* (blue) David P. Bartel. cell. 2004

  7. The molecular hallmarks of lin-4 Lin He and Gregory J.Hannon. Nature. 2004

  8. MiRNAs and SiRNAs — what’s the difference • terms of their molecular characteristics, biogenesis and effector functions • share a common RNase-III processing enzyme, Dicer, and closely related effector complexes, RISCs, for post-transcriptional repression miRNA siRNA • Specific precursor • bind to the target 3′ UTRs through imperfect complementarity at multiple • sites • sampled more randomly from long dsRNAs • form a perfect duplex with their targets at only one site

  9. The current model for the biogenesis and post-transcriptional suppression Two processing First: nascent miRNA(pri-miRNA) → ~70nt precursor (pre-miRNA) Second: → 21~25nt mature miRNA Drosha, Dicer: ds RNA specific endonuclease Lin He and Gregory J.Hannon. Nature. 2004

  10. The structure and function of the Dicer family • Dicer1 and Dicer2 • Deficiency in Dicer1 disrupts the processing of pre-miRNAs • loss of Dicer2 affects the production of siRNAs, but not miRNA maturation. • =PAZ domain is only present in Dicer1, but absent in Dicer2 Argonaute (AGO) proteins include PAZ domain and a piwi domain. Lin He and Gregory J.Hannon. Nature. 2004

  11. Post-transcriptional repression by miRNAs • Lin-4와 lin-14 • Let-7(worms), Bantam(flies), miR30 (mammal) – negatively regulate • mir-196 = animal에서 유일하게 그 target인 Hoxb8에서 base pairing이 perfect하여 mRNA의 destruction일으킴 • miR-172 = 유일하게 coding 영역에 존재하며 plant에서 유일하게 repressor로 작용

  12. C. elegans : 116 • C. briggsae : 50 • D. melanogaster : 78 • thaliana : 48 • Rice : 28 • Mouse : 207 • Rat : 185 • Human : 191

  13. miR-26a and miR-99a expression is reduced in human lung cancer cell line.

  14. In vitro processing of miRNA by Drosha

  15. AGO protein 2004.08.05

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