title: Perlman syndrome nuclease DIS3L2 controls cytoplasmic non-coding RNAs and provides surveillance pathway for maturing snRNAs.
abstract: The exosome-independent exoribonuclease DIS3L2 is mutated in Perlman syndrome. Here, we used extensive global transcriptomic and targeted biochemical analyses to identify novel DIS3L2 substrates in human cells. We show that DIS3L2 regulates pol II transcripts, comprising selected canonical and histone-coding mRNAs, and a novel FTL_short RNA from the ferritin mRNA 5' UTR. Importantly, DIS3L2 contributes to surveillance of maturing snRNAs during their cytoplasmic processing. Among pol III transcripts, DIS3L2 particularly targets vault and Y RNAs and an Alu-like element BC200 RNA, but not Alu repeats, which are removed by exosome-associated DIS3. Using 3' RACE-Seq, we demonstrate that all novel DIS3L2 substrates are uridylated in vivo by TUT4/TUT7 poly(U) polymerases. Uridylation-dependent DIS3L2-mediated decay can be recapitulated in vitro, thus reinforcing the tight cooperation between DIS3L2 and TUTases. Together these results indicate that catalytically inactive DIS3L2, characteristic of Perlman syndrome, can lead to deregulation of its target RNAs to disturb transcriptome homeostasis.
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Łabno
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Warkocki
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Kuliński
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Paweł Szczepan
authors.initials: PS
authors.lastname: Krawczyk
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Krystian
authors.initials: K
authors.lastname: Bijata
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland rtom1916@gmail.com.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Rafał
authors.initials: R
authors.lastname: Tomecki
authors.affiliation: Institute of Biochemistry and Biophysics, Polish Academy of Sciences, 02-106 Warsaw, Poland andrzejd@ibb.waw.pl.|Department of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, 02-106 Warsaw, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dziembowski
mesh_terms: D020087:Alu Elements; D002460:Cell Line; D005095:Exoribonucleases / Q000378:metabolism*; D005320:Fetal Macrosomia / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D011485:Protein Binding; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012342:RNA, Small Nuclear / Q000235:genetics* / Q000378:metabolism*; D022661:RNA, Untranslated / Q000235:genetics* / Q000378:metabolism*; D013379:Substrate Specificity; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D012342:RNA, Small Nuclear; D022661:RNA, Untranslated; C571454:DIS3L2 protein, human; D005095:Exoribonucleases