title: A role for the Perlman syndrome exonuclease Dis3l2 in the Lin28-let-7 pathway.
abstract: The pluripotency factor Lin28 blocks the expression of let-7 microRNAs in undifferentiated cells during development, and functions as an oncogene in a subset of cancers. Lin28 binds to let-7 precursor (pre-let-7) RNAs and recruits 3' terminal uridylyl transferases to selectively inhibit let-7 biogenesis. Uridylated pre-let-7 is refractory to processing by Dicer, and is rapidly degraded by an unknown RNase. Here we identify Dis3l2 as the 3'-5' exonuclease responsible for the decay of uridylated pre-let-7 in mouse embryonic stem cells. Biochemical reconstitution assays show that 3' oligouridylation stimulates Dis3l2 activity in vitro, and knockdown of Dis3l2 in mouse embryonic stem cells leads to the stabilization of pre-let-7. Our study establishes 3' oligouridylation as an RNA decay signal for Dis3l2, and identifies the first physiological RNA substrate of this new exonuclease, which is mutated in the Perlman syndrome of fetal overgrowth and causes a predisposition to Wilms' tumour development.
authors.affiliation: Stem Cell Program, Boston Children's Hospital, Massachusetts 02115, USA.
authors.forename: Hao-Ming
authors.initials: HM
authors.lastname: Chang
authors.forename: Robinson
authors.initials: R
authors.lastname: Triboulet
authors.forename: James E
authors.initials: JE
authors.lastname: Thornton
authors.forename: Richard I
authors.initials: RI
authors.lastname: Gregory
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism; D005092:Exonucleases / Q000378:metabolism*; D005095:Exoribonucleases / Q000378:metabolism*; D005320:Fetal Macrosomia / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism*; D013379:Substrate Specificity; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000378:metabolism; D009396:Wilms Tumor / Q000201:enzymology* / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
chemical_list: C488352:Lin-28 protein, mouse; D035683:MicroRNAs; D012322:RNA Precursors; D016601:RNA-Binding Proteins; C542687:mirnlet7 microRNA, mouse; C031034:3'-uridylic acid; D014542:Uridine Monophosphate; C581306:Dis3l2 protein, mouse; D005092:Exonucleases; D005095:Exoribonucleases; D012260:Ribonucleases