title: Exonuclease hDIS3L2 specifies an exosome-independent 3'-5' degradation pathway of human cytoplasmic mRNA.
abstract: Turnover of mRNA in the cytoplasm of human cells is thought to be redundantly conducted by the monomeric 5'-3' exoribonuclease hXRN1 and the 3'-5' exoribonucleolytic RNA exosome complex. However, in addition to the exosome-associated 3'-5' exonucleases hDIS3 and hDIS3L, the human genome encodes another RNase II/R domain protein-hDIS3L2. Here, we show that hDIS3L2 is an exosome-independent cytoplasmic mRNA 3'-5' exonuclease, which exhibits processive activity on structured RNA substrates in vitro. hDIS3L2 associates with hXRN1 in an RNA-dependent manner and can, like hXRN1, be found on polysomes. The impact of hDIS3L2 on cytoplasmic RNA metabolism is revealed by an increase in levels of cytoplasmic RNA processing bodies (P-bodies) upon hDIS3L2 depletion, which also increases half-lives of investigated mRNAs. Consistently, RNA sequencing (RNA-seq) analyses demonstrate that depletion of hDIS3L2, like downregulation of hXRN1 and hDIS3L, causes changed levels of multiple mRNAs. We suggest that hDIS3L2 is a key exosome-independent effector of cytoplasmic mRNA metabolism.
authors.affiliation: Centre for mRNP Biogenesis and Metabolism, Aarhus University, Aarhus C, Denmark.
authors.forename: Michal
authors.initials: M
authors.lastname: Lubas
authors.forename: Christian K
authors.initials: CK
authors.lastname: Damgaard
authors.forename: Rafal
authors.initials: R
authors.lastname: Tomecki
authors.forename: Dominik
authors.initials: D
authors.lastname: Cysewski
authors.forename: Torben Heick
authors.initials: TH
authors.lastname: Jensen
authors.forename: Andrzej
authors.initials: A
authors.lastname: Dziembowski
mesh_terms: D015152:Blotting, Northern; D003593:Cytoplasm / Q000378:metabolism*; D005095:Exoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics / Q000378:metabolism; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008830:Microbodies / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011132:Polyribosomes / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D008869:Microtubule-Associated Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C571454:DIS3L2 protein, human; D005095:Exoribonucleases; D063326:Exosome Multienzyme Ribonuclease Complex; C470512:XRN1 protein, human