Apoptosis is a tightly coordinated cell death program that damages mitochondria DNA proteins and membrane lipids. arrest and cell death whereas overexpression enhances cell death. Our results suggest that global mRNA decay is an overlooked hallmark of apoptosis. Abstract INTRODUCTION Mitochondrial outer membrane permeabilization (MOMP) and caspase activation are prominent shared events triggered by classical apoptotic stimuli including DNA-damaging agents death receptor signaling and cytotoxic lymphocyte attack (Taylor et al. 2008 MOMP releases cytochrome from the mitochondrial intermembrane space into the cytosol where it drives the assembly of the apoptosome the molecular scaffold that activates caspase 9 which cleaves and activates the effector caspase zymogens notably caspase 3 (Riedl and Shi 2004 The effector caspases cleave hundreds of substrates to cause cell death. The apoptotic program dismantles the cellular repair machinery as the cell self-destructs. Pre-mRNA splicing and RNA nuclear export are inhibited to prevent stress-responsive mRNAs from being translated (Rajani et al. 2012 New protein synthesis is blocked ostensibly through translation initiation factor alterations that include eIF4G cleavage and eIF2α phosphorylation (Holcik and Sonenberg 2005 Morley et al. 2005 Taylor et al. 2008 However eiF4G cleavage is dispensable for translation arrest (Jeffrey et al. 2002 and eIF2α phosphorylation and eIF4G cleavage occur after translation is alpha-hederin inhibited (Saelens et al. 2001 Thus other mechanisms are needed to explain the block in alpha-hederin translation during apoptosis (Thomas and Lieberman 2013 Human mRNAs are generally very stable with a mean half-life of ~7 hr (Tani et al. 2012 Under normal conditions most mRNAs decay via deadenylation followed by decapping and exonucleolytic decay from the 5′ and 3′ ends by XRN1 and the exosome respectively (Schoenberg and Maquat 2012 Little is known about what happens to RNA during apoptosis. 28S rRNA is cleaved late in cell death (Degen et al. 2000 but not in all dying cells. Several studies have recommended that the degrees of some mRNAs decrease during cell loss of life (Bushell et al. 2004 Del Prete et al. 2002 Latest work shows that 3′ uridylation may also act as a sign for RNA turnover (Norbury 2013 Nontemplated uridylate residues added by terminal uridylyl transferases (TUTases) have already been entirely on histone mRNAs (Mullen and Marzluff 2008 Rissland and Norbury 2009 Schmidt et al. 2011 Slevin et al. 2014 pre-miRNAs (Thornton et al. 2012 and mRNAs at miRNA cleavage sites (Shen and Goodman 2004 The TUTases ZCCHC11 (TUT4) and ZCCHC6 (TUT7) uridylate miRNAs (Thornton et al. alpha-hederin 2012 2014 whereas ZCCHC11 uridylates histone mRNAs (Schmidt et al. 2011 Human being cells communicate three homologous 3′ to 5′ exoribonucleases: DIS3 DIS3L1 and DIS3L2. The 1st two are mainly from the nuclear (DIS3) and cytosolic (DIS3L1) exosome but DIS3L2 isn’t (Lubas et al. 2013 DIS3L2 which preferentially degrades RNAs with 3′ uridylate residues continues to be implicated in degradation of uridylated pre-miRNAs (Chang et al. 2013 Ustianenko et al. 2013 in human being cells and mRNAs in fission candida (Malecki et al. 2013 alpha-hederin Knock-down of human being also prolongs the half-life SGK of mammalian polyadenylated mRNAs (Lubas et al. 2013 suggesting that it could degrade mRNAs also. Here we display that global decay of mRNAs however not noncoding RNAs (ncRNAs) happens early after induction of apoptosis induced by varied traditional apoptotic stimuli. Decay can be activated by MOMP and starts around enough time of caspase activation and before DNA degradation. mRNA decay intermediates are uridylated near the stop codon by the TUTases ZCCHC6 and ZCCHC11. The uridylated intermediates are further degraded by DIS3L2. mRNA decay promotes cell death since cells better survive apoptotic stimuli after knockdown of overexpression and transcription inhibitors enhance apoptosis. These results support the concept that global mRNA decay is alpha-hederin a hallmark of cell death that may amplify apoptotic signaling. Further work is required to delineate the trigger and the complete apoptotic mRNA decay pathway. RESULTS.