RNA interference - gene silencing by double-stranded RNA:The 2006 Nobel Prize for Physiology or Medicine

摘要

The classical view of the flow of geneticinformation at the molecular level envisages that within a living cell, the information encoded in the master molecule,the deoxyribonucleic acid (DNA), is firsttranscribed into RNA with the help of anRNA polymrase enzyme, and is thentranslated into proteins using the proteinsynthesis machinery available within thecell (Figure 1). This flow of genetic information from DNA via mRNA to proteinwas termed the central dogma of molecular biology by the British Nobel LaureateFrancis Crick. However, except for somehousekeeping genes, synthesis of proteinsdue to individual genes is not constitutive, and is now known to be regulated atdifferent levels. For instance, initially inearly 1960s, it was shown that the codingsequences in bacteria and other prokar-yotes are organized in operons, which areunder the control of regulator, promoterand operator genes. This work was recognized by the award of 1965 Nobel Prizefor Physiology or Medicine to FranfoisJacob, Jacques Monod and Andr6 Lwoff.Several modifications of central dogmaand the classical operon concept werediscovered later during 1970s, 1980s and1990s. For instance, in 1970, it wasshown that in some RNA viruses, RNAcan be used for the synthesis of DNA (asan intermediate molecule) using an enzymenow popularly described as reverse tran-scriptase; this discovery was recognizedby the award of 1975 Nobel Prize forPhysiology or Medicine to David Baltimore,Renato Dulbecco and Howard Temin.During early 1980s, it was also shownthat the genetic information within a eu-karyotic cell occurs as split genes withintron and exon sequences, and that in-tron sequences are spliced out after transcription during RNA processing. Thisdiscovery was recognized by the awardof 1993 Nobel Prize for Physiology orMedicine to Richard J. Roberts and PhillipA. Sharp. More recently during mid-1990s,it was shown that a large part of DNA ineukaryotes is actually used for synthesisof non-coding RNA (ncRNA), whichplays an important role in regulating theexpression of genes at the post-transcri-ptional level. It was shown that the ncRNAgives rise to double-stranded RNA(dsRNA), which is responsible for genesilencing; the phenomenon was describedas RNA interference (RNAi). This 'discovery of RNAi involving gene silencingby dsRNA' has been recognized by theaward of the 2006 Nobel Prize for Physiology or Medicine to two American scientists, Andrew Fire and Craig C. Mello.They reported for the first time in 1998that in a very specific manner, gene silencing can be achieved through dsRNA-mediated degradation of mRNA~1. Thismechanism of RNAi is activated whenspecific RNA molecules occur in the cellas dsRNA, which activates biochemicalmachinery degrading mRNA moleculeshaving nucleotide sequence identical tothat of the dsRNA. When such mRNAmolecules disappear due to dsRNA-mediated degradation, obviously the corresponding protein cannot be synthesized, so that the corresponding gene isapparently silenced.