2. Academic Validation
  3. Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

Uridylation by TUT4/7 Restricts Retrotransposition of Human LINE-1s

  • Cell. 2018 Sep 6;174(6):1537-1548.e29. doi: 10.1016/j.cell.2018.07.022.
Zbigniew Warkocki 1,  Paweł S Krawczyk 2,  Dorota Adamska 2,  Krystian Bijata 2,  Jose L Garcia-Perez 3,  Andrzej Dziembowski 4
Affiliations

Affiliations

  • 1 Laboratory of RNA Biology and Functional Genomics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland. Electronic address: zwarkoc@gmail.com.
  • 2 Laboratory of RNA Biology and Functional Genomics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland.
  • 3 Department of Genomic Medicine, Centre for Genomics and Oncology (Pfizer-University of Granada and Andalusian Regional Government), PTS Granada, Granada 18016, Spain; Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.
  • 4 Laboratory of RNA Biology and Functional Genomics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland; Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Pawinskiego 5a, 02-106 Warsaw, Poland. Electronic address: andrzejd@ibb.waw.pl.
PMID: 30122351 DOI: 10.1016/j.cell.2018.07.022
Abstract

LINE-1 retrotransposition is tightly restricted by layers of regulatory control, with epigenetic pathways being the best characterized. Looking at post-transcriptional regulation, we now show that LINE-1 mRNA 3' ends are pervasively uridylated in various human cellular models and in mouse testes. TUT4 and TUT7 uridyltransferases catalyze the modification and function in cooperation with the helicase/RNPase MOV10 to counteract the RNA chaperone activity of the L1-ORF1p retrotransposon protein. Uridylation potently restricts LINE-1 retrotransposition by a multilayer mechanism depending on differential subcellular localization of the uridyltransferases. We propose that uridine residues added by TUT7 in the cytoplasm inhibit initiation of reverse transcription of LINE-1 mRNAs once they are reimported to the nucleus, whereas uridylation by TUT4, which is enriched in cytoplasmic foci, destabilizes mRNAs. These results provide a model for the post-transcriptional restriction of LINE-1, revealing a key physiological role for TUT4/7-mediated uridylation in maintaining genome stability.

Keywords

3′ RACE-seq; L1-ORF1p; L1-ORF2p; LINE-1; MOV10; TUT4; TUT7; poly(A); retrotransposition; uridylation.

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