Ruvkun discovered the mechanism by whichlin-4, the firstmicroRNA (miRNA) discovered byVictor Ambros, regulates the translation of targetmessenger RNAs via imperfect base-pairing to those targets, and discovered the second miRNA,let-7, and that it is conserved across animal phylogeny, including in humans. These miRNA discoveries revealed a new world ofRNA regulation at an unprecedented small size scale, and the mechanism of that regulation. Ruvkun also discovered many features of insulin-like signaling in the regulation ofaging andmetabolism.
Ruvkun's research revealed that the miRNAlin-4, a 22 nucleotide regulatory RNA discovered in 1992 byVictor Ambros' lab, regulates its target mRNAlin-14 by forming imperfect RNA duplexes to down-regulate translation. The first indication that the key regulatory element of thelin-14 gene recognized by thelin-4 gene product was in thelin-14 3’ untranslated region came from the analysis oflin-14 gain-of-function mutations which showed that they are deletions of conserved elements in thelin-14 3’ untranslated region. Deletion of these elements relieves the normal late stage-specific repression of LIN-14 protein production, andlin-4 is necessary for that repression by the normallin-14 3' untranslated region.[8][9] In a key breakthrough, the Ambros lab discovered thatlin-4 encodes a very small RNA product, defining the 22 nucleotide miRNAs. When Ambros and Ruvkun compared the sequence of thelin-4 miRNA and thelin-14 3’ untranslated region, they discovered that thelin-4 RNA base pairs with conserved bulges and loops to the 3’ untranslated region of thelin-14 target mRNA, and that thelin-14 gain of function mutations delete theselin-14 complementary sites to relieve the normal repression of translation bylin-4. In addition, they showed that thelin-14 3' untranslated region could confer thislin-4-dependent translational repression on unrelated mRNAs by creating chimeric mRNAs that werelin-4-responsive. In 1993, Ruvkun reported in the journalCell on the regulation oflin-14 bylin-4.[10] In the same issue ofCell,Victor Ambros described the regulatory product oflin-4 as a small RNA.[11] These papers revealed a new world of RNA regulation at an unprecedented small size scale, and the mechanism of that regulation.[12][13] Together, this research is now recognized as the first description ofmicroRNAs and the mechanism by which partially base-paired miRNA::mRNA duplexes inhibit translation.[14]
In 2000, the Ruvkun lab reported the identification of secondC. elegans microRNA,let-7, which like the first microRNA regulates translation of the target gene, in this caselin-41, via imperfect base pairing to the 3’ untranslated region of that mRNA.[15][16] This was an indication that miRNA regulation via 3’ UTR complementarity may be a common feature, and that there were likely to be more microRNAs. The generality of microRNA regulation to other animals was established by the Ruvkun lab later in 2000, when they reported that the sequence and regulation of thelet-7 microRNA is conserved across animal phylogeny, including in humans.[17]
When siRNAs of the same 21-22 nucleotide size aslin-4 andlet-7 were discovered in 1999 by Hamilton and Baulcombe in plants,[18] the fields of RNAi and miRNAs suddenly converged. It seemed likely that the similarly sized miRNAs and siRNAs would use similar mechanisms. In a collaborative effort, the Mello and Ruvkun labs showed that the first known components ofRNA interference and their paralogs, Dicer and the PIWI proteins, are used by both miRNAs and siRNAs.[19] Ruvkun's lab in 2003 identified many more miRNAs,[20][21] identified miRNAs from mammalian neurons,[22] and in 2007 discovered many new protein-cofactors for miRNA function.[23][24][25]
Ruvkun's laboratory has also discovered that an insulin-like signaling pathway controlsC. elegans metabolism and longevity. Klass[26] Johnson[27] andKenyon[28] showed that the developmental arrest program mediated by mutations inage-1 anddaf-2 increaseC. elegans longevity. The Ruvkun lab established that these genes constitute an insulin like receptor and a downstream phosphatidylinositol kinase that couple to thedaf-16 gene product, a highly conserved Forkhead transcription factor.[29] Homologues of these genes have now been implicated in regulation of human aging.[30] These findings are also important for diabetes, since the mammalian orthologs ofdaf-16 (referred to as FOXO transcription factors) are also regulated by insulin.[31] The Ruvkun lab has used full genome RNAi libraries to discover genes that regulate aging and metabolism. Many of these genes are broadly conserved in animal phylogeny and could be targeted in diabetes drug development.[32]
The Ruvkun lab in collaboration withMaria Zuber atMIT, Chris Carr (now at Georgia Tech), and Michael Finney (now a San Francisco biotech entrepreneur) has been developing protocols and instruments that can amplify and sequence DNA and RNA to search for life on another planet that is ancestrally related to the Tree of Life on Earth.[33] The Search for Extraterrestrial Genomes, or SETG, project has been developing a small instrument that can determine DNA sequences on Mars (or any other planetary body), and send the information in those DNA sequence files to Earth for comparison to life on Earth.[34]
In 2012, Ruvkun made an original contribution to the field of immunology with the publication of a featured paper in the journalCell describing an elegant mechanism for innate immune surveillance in animals that relies on the monitoring of core cellular functions in the host, which are often sabotaged by microbial toxins during the course of infection.[35]
In 2019, Ruvkun, together with Chris Carr, Mike Finney andMaria Zuber,[36] presented the argument that the appearance of sophisticated microbial life on Earth soon after it cooled, and the recent discoveries ofhot Jupiters and disruptive planetary migrations in exoplanet systems favors the spread of DNA-based microbial life across the galaxy. The SETG project is working to haveNASA send aDNA sequencer toMars tosearch for life there in the hope thatevidence will be uncovered that life did not ariseoriginally on Earth, butelsewhere in the universe.[37]
As of 2018, Ruvkun has published about 150 scientific articles. Ruvkun has received numerous awards for his contributions to medical science, for his contributions to the aging field[38] and to the discovery ofmicroRNAs.[39] He is a recipient of theLasker Award for Basic Medical Research,[40] theGairdner Foundation International Award, and the Benjamin Franklin Medal in Life Science.[41] Ruvkun was elected as a member of theNational Academy of Sciences in 2008.[42]
^Ruvkun, G; Wightman, B; Bürglin, T; Arasu, P (1991). "Dominant gain-of-function mutations that lead to misregulation of the C. Elegans heterochronic gene lin-14, and the evolutionary implications of dominant mutations in pattern-formation genes".Development. Supplement.1:47–54.PMID1742500.
^Reinhart, B. J.; Slack, F. J.; Basson, M.; Pasquinelli, A. E.; Bettinger, J. C.; Rougvie, A. E.; Horvitz, H. R.; Ruvkun, G. (2000). "The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans".Nature.403 (6772):901–906.Bibcode:2000Natur.403..901R.doi:10.1038/35002607.PMID10706289.S2CID4384503.
^Pasquinelli, A. E.; Reinhart, B. J.; Slack, F.; Martindale, M. Q.; Kuroda, M. I.; Maller, B.; Hayward, D. C.; Ball, E. E.; Degnan, B.; Müller, B.; Spring, P.; Srinivasan, J. R.; Fishman, A.; Finnerty, M.; Corbo, J.; Levine, J.; Leahy, M.; Davidson, P.; Ruvkun, E. (2000). "Conservation of the sequence and temporal expression of let-7 heterochronic regulatory RNA".Nature.408 (6808):86–89.Bibcode:2000Natur.408...86P.doi:10.1038/35040556.PMID11081512.S2CID4401732.
^Hamilton, A. J.; Baulcombe, D. C. (1999). "A species of small antisense RNA in posttranscriptional gene silencing in plants".Science.286 (5441):950–952.doi:10.1126/science.286.5441.950.PMID10542148.
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