title: Apoptosis Triggers Specific, Rapid, and Global mRNA Decay with 3' Uridylated Intermediates Degraded by DIS3L2.
abstract: Apoptosis is a tightly coordinated cell death program that damages mitochondria, DNA, proteins, and membrane lipids. Little is known about the fate of RNA as cells die. Here, we show that mRNAs, but not noncoding RNAs, are rapidly and globally degraded during apoptosis. mRNA decay is triggered early in apoptosis, preceding membrane lipid scrambling, genomic DNA fragmentation, and apoptotic changes to translation initiation factors. mRNA decay depends on mitochondrial outer membrane permeabilization and is amplified by caspase activation. 3' truncated mRNA decay intermediates with nontemplated uridylate-rich tails are generated during apoptosis. These tails are added by the terminal uridylyl transferases (TUTases) ZCCHC6 and ZCCHC11, and the uridylated transcript intermediates are degraded by the 3' to 5' exonuclease DIS3L2. Knockdown of DIS3L2 or the TUTases inhibits apoptotic mRNA decay, translation arrest, and cell death, whereas DIS3L2 overexpression enhances cell death. Our results suggest that global mRNA decay is an overlooked hallmark of apoptosis.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Marshall P
authors.initials: MP
authors.lastname: Thomas
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Whangbo
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: McCrossan
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Keri B
authors.initials: KB
authors.lastname: Sanborn
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Emre
authors.initials: E
authors.lastname: Basar
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Walch
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: judy.lieberman@childrens.harvard.edu.
authors.forename: Judy
authors.initials: J
authors.lastname: Lieberman
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D005095:Exoribonucleases / Q000378:metabolism*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D016133:Polymerase Chain Reaction; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D020871:RNA Stability / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C511130:TUT4 protein, human; D012316:RNA Nucleotidyltransferases; C576505:TUT7 protein, human; C571454:DIS3L2 protein, human; D005095:Exoribonucleases