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Protein Cell. 2010 September; 1(9): 795–801.
Published online 2010 October 7. doi:  10.1007/s13238-010-0107-x
PMCID: PMC2992325

Apoptotic regulation and tRNA


Apoptotic regulation is critical to organismal homeostasis and protection against many human disease processes such as cancer. Significant research efforts over the past several decades have illuminated many signaling molecules and effecter proteins responsible for this form of programmed cell death. Recent evidence suggests that transfer RNA (tRNA) regulates apoptotic sensitivity at the level of cytochrome c-mediated apoptosome formation. This finding unexpectedly places tRNA at the nexus of cellular biosynthesis and survival. Here we review the current understanding of both the apoptotic machinery and tRNA biology. We describe the evidence linking tRNA and cytochrome c in depth, and speculate on the implications of this link in cell biology.

Keywords: apoptotic regulation, tRNA, cytochrome c


  • Acehan D., Jiang X., Morgan D.G., Heuser J.E., Wang X., Akey C.W. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell. 2002;9:423–432. doi: 10.1016/S1097-2765(02)00442-2. [PubMed] [Cross Ref]
  • Adams J.M., Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281:1322–1326. doi: 10.1126/science.281.5381.1322. [PubMed] [Cross Ref]
  • Ashkenazi A., Dixit V.M. Death receptors: signaling and modulation. Science. 1998;281:1305–1308. doi: 10.1126/science.281.5381.1305. [PubMed] [Cross Ref]
  • Bao Q., Lu W., Rabinowitz J.D., Shi Y. Calcium blocks formation of apoptosome by preventing nucleotide exchange in Apaf-1. Mol Cell. 2007;25:181–192. doi: 10.1016/j.molcel.2006.12.013. [PubMed] [Cross Ref]
  • Beere H.M., Wolf B.B., Cain K., Mosser D.D., Mahboubi A., Kuwana T., Tailor P., Morimoto R.I., Cohen G.M., Green D. R. Heat-shock protein 70 inhibits apoptosis by preventing recruitment of procaspase-9 to the Apaf-1 apoptosome. Nat Cell Biol. 2000;2:469–475. doi: 10.1038/35019501. [PubMed] [Cross Ref]
  • Boatright K.M., Renatus M., Scott F.L., Sperandio S., Shin H., Pedersen I.M., Ricci J.E., Edris W.A., Sutherlin D.P., Green D. R., et al. A unified model for apical caspase activation. Mol Cell. 2003;11:529–541. doi: 10.1016/S1097-2765(03)00051-0. [PubMed] [Cross Ref]
  • Bruey J.M., Ducasse C., Bonniaud P., Ravagnan L., Susin S.A., Diaz-Latoud C., Gurbuxani S., Arrigo A.P., Kroemer G., Solary E., et al. Hsp27 negatively regulates cell death by interacting with cytochrome c. Nat Cell Biol. 2000;2:645–652. doi: 10.1038/35023595. [PubMed] [Cross Ref]
  • Cain K., Langlais C., Sun X.M., Brown D.G., Cohen G.M. Physiological concentrations of K+ inhibit cytochrome cdependent formation of the apoptosome. J Biol Chem. 2001;276:41985–41990. doi: 10.1074/jbc.M107419200. [PubMed] [Cross Ref]
  • Chandra D., Bratton S.B., Person M.D., Tian Y., Martin A.G., Ayres M., Fearnhead H.O., Gandhi V., Tang D.G. Intracellular nucleotides act as critical prosurvival factors by binding to cytochrome C and inhibiting apoptosome. Cell. 2006;125:1333–1346. doi: 10.1016/j.cell.2006.05.026. [PubMed] [Cross Ref]
  • Chang D.W., Xing Z., Capacio V.L., Peter M.E., Yang X. Interdimer processing mechanism of procaspase-8 activation. EMBO J. 2003;22:4132–4142. doi: 10.1093/emboj/cdg414. [PubMed] [Cross Ref]
  • Chang H.Y., Yang X. Proteases for cell suicide: functions and regulation of caspases. Microbiol Mol Biol Rev. 2000;64:821–846. doi: 10.1128/MMBR.64.4.821-846.2000. [PMC free article] [PubMed] [Cross Ref]
  • Chipuk J.E., Green D.R. How do BCL-2 proteins induce mitochondrial outer membrane permeabilization? Trends Cell Biol. 2008;18:157–164. doi: 10.1016/j.tcb.2008.01.007. [PMC free article] [PubMed] [Cross Ref]
  • Cole C., Sobala A., Lu C., Thatcher S.R., Bowman A., Brown J.W., Green P.J., Barton G.J., Hutvagner G. Filtering of deep sequencing data reveals the existence of abundant Dicerdependent small RNAs derived from tRNAs. RNA. 2009;15:2147–2160. doi: 10.1261/rna.1738409. [PubMed] [Cross Ref]
  • Costanzi J., Sidransky D., Navon A., Goldsweig H. Ribonucleases as a novel pro-apoptotic anticancer strategy: review of the preclinical and clinical data for ranpirnase. Cancer Invest. 2005;23:643–650. doi: 10.1080/07357900500283143. [PubMed] [Cross Ref]
  • Crighton D., Woiwode A., Zhang C., Mandavia N., Morton J.P., Warnock L.J., Milner J., White R.J., Johnson D.L. p53 represses RNA polymerase III transcription by targeting TBP and inhibiting promoter occupancy by TFIIIB. EMBO J. 2003;22:2810–2820. doi: 10.1093/emboj/cdg265. [PubMed] [Cross Ref]
  • Datta S.R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M.E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997;91:231–241. doi: 10.1016/S0092-8674(00)80405-5. [PubMed] [Cross Ref]
  • de Bruijn M.H., Klug A. A model for the tertiary structure of mammalian mitochondrial transfer RNAs lacking the entire ‘dihydrouridine’ loop and stem. EMBO J. 1983;2:1309–1321. [PubMed]
  • Elbarbary R.A., Takaku H., Uchiumi N., Tamiya H., Abe M., Nishida H., Nashimoto M. Human cytosolic tRNase ZL can downregulate gene expression through miRNA. FEBS Lett. 2009;583:3241–3246. doi: 10.1016/j.febslet.2009.09.015. [PubMed] [Cross Ref]
  • Elbarbary R.A., Takaku H., Uchiumi N., Tamiya H., Abe M., Takahashi M., Nishida H., Nashimoto M., Randau L. Modulation of gene expression by human cytosolic tRNase Z(L) through 5′-half-tRNA. PLoS ONE. 2009;4:e5908. doi: 10.1371/journal.pone.0005908. [PMC free article] [PubMed] [Cross Ref]
  • Gomez-Roman, N., Felton-Edkins, Z.A., Kenneth, N.S., Goodfellow, S.J., Athineos, D., Zhang, J., Ramsbottom, B.A., Innes, F., Kantidakis, T., Kerr, E.R., et al. (2006). Activation by c-Myc of transcription by RNA polymerases I, II and III. Biochem Soc Symp, 141–154. [PubMed]
  • Hinnebusch A.G. Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol. 2005;59:407–450. doi: 10.1146/annurev.micro.59.031805.133833. [PubMed] [Cross Ref]
  • Huang D.C., Strasser A. BH3-Only proteins-essential initiators of apoptotic cell death. [In Process Citation] Cell. 2000;103:839–842. [PubMed]
  • Iordanov M.S., Ryabinina O.P., Wong J., Dinh T.H., Newton D.L., Rybak S.M., Magun B.E. Molecular determinants of apoptosis induced by the cytotoxic ribonuclease onconase: evidence for cytotoxic mechanisms different from inhibition of protein synthesis. Cancer Res. 2000;60:1983–1994. [PubMed]
  • Jiang X., Kim H.E., Shu H., Zhao Y., Zhang H., Kofron J., Donnelly J., Burns D., Ng S.C., Rosenberg S., et al. Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science. 2003;299:223–226. doi: 10.1126/science.1076807. [PubMed] [Cross Ref]
  • Kamhi E., Raitskin O., Sperling R., Sperling J. A potential role for initiator-tRNA in pre-mRNA splicing regulation. Proc Natl Acad Sci U S A. 2010;107:11319–11324. doi: 10.1073/pnas.0911561107. [PubMed] [Cross Ref]
  • Kim H.E., Du F., Fang M., Wang X. Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci U S A. 2005;102:17545–17550. doi: 10.1073/pnas.0507900102. [PubMed] [Cross Ref]
  • Kim H.E., Jiang X., Du F., Wang X. PHAPI, CAS, and Hsp70 promote apoptosome formation by preventing Apaf-1 aggregation and enhancing nucleotide exchange on Apaf-1. Mol Cell. 2008;30:239–247. doi: 10.1016/j.molcel.2008.03.014. [PubMed] [Cross Ref]
  • Kleiman L., Jones C.P., Musier-Forsyth K. Formation of the tRNALys packaging complex in HIV-1. FEBS Lett. 2010;584:359–365. doi: 10.1016/j.febslet.2009.11.038. [PMC free article] [PubMed] [Cross Ref]
  • Larminie C.G., Sutcliffe J.E., Tosh K., Winter A.G., Felton-Edkins Z.A., White R.J. Activation of RNA polymerase III transcription in cells transformed by simian virus 40. Mol Cell Biol. 1999;19:4927–4934. doi: 10.1128/MCB.19.7.4927. [PMC free article] [PubMed] [Cross Ref]
  • Lee Y.S., Shibata Y., Malhotra A., Dutta A. A novel class of small RNAs: tRNA-derived RNA fragments (tRFs) Genes Dev. 2009;23:2639–2649. doi: 10.1101/gad.1837609. [PubMed] [Cross Ref]
  • Li J., Yuan J. Caspases in apoptosis and beyond. Oncogene. 2008;27:6194–6206. doi: 10.1038/onc.2008.297. [PubMed] [Cross Ref]
  • Liu X., Kim C.N., Yang J., Jemmerson R., Wang X. Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c. Cell. 1996;86:147–157. doi: 10.1016/S0092-8674(00)80085-9. [PubMed] [Cross Ref]
  • Lowe T.M., Eddy S.R. tRNAscan-SE: a program for improved detection of transfer RNA genes in genomic sequence. Nucleic Acids Res. 1997;25:955–964. doi: 10.1093/nar/25.5.0955. [PMC free article] [PubMed] [Cross Ref]
  • Marshall L., Kenneth N.S., White R.J. Elevated tRNA (iMet) synthesis can drive cell proliferation and oncogenic transformation. Cell. 2008;133:78–89. doi: 10.1016/j.cell.2008.02.035. [PubMed] [Cross Ref]
  • Martin A.G., Fearnhead H.O. Apocytochrome c blocks caspase-9 activation and Bax-induced apoptosis. J Biol Chem. 2002;277:50834–50841. doi: 10.1074/jbc.M209369200. [PubMed] [Cross Ref]
  • Mei Y., Yong J., Liu H., Shi Y., Meinkoth J., Dreyfuss G., Yang X. tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell. 2010;37:668–678. doi: 10.1016/j.molcel.2010.01.023. [PMC free article] [PubMed] [Cross Ref]
  • Mesner P.W., Jr, Bible K.C., Martins L.M., Kottke T.J., Srinivasula S. M., Svingen P.A., Chilcote T.J., Basi G.S., Tung J.S., Krajewski S., et al. Characterization of caspase processing and activation in HL-60 cell cytosol under cell-free conditions. Nucleotide requirement and inhibitor profile. J Biol Chem. 1999;274:22635–22645. doi: 10.1074/jbc.274.32.22635. [PubMed] [Cross Ref]
  • Pandey P., Saleh A., Nakazawa A., Kumar S., Srinivasula S.M., Kumar V., Weichselbaum R., Nalin C., Alnemri E.S., Kufe D., et al. Negative regulation of cytochrome c-mediated oligomerization of Apaf-1 and activation of procaspase-9 by heat shock protein 90. EMBO J. 2000;19:4934–4322. doi: 10.1093/emboj/19.16.4310. [PubMed] [Cross Ref]
  • Pavon-Eternod M., Gomes S., Geslain R., Dai Q., Rosner M.R., Pan T. tRNA over-expression in breast cancer and functional consequences. Nucleic Acids Res. 2009;37:7268–7280. doi: 10.1093/nar/gkp787. [PMC free article] [PubMed] [Cross Ref]
  • Riedl S.J., Salvesen G.S. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol. 2007;8:405–413. doi: 10.1038/nrm2153. [PubMed] [Cross Ref]
  • Ruggero D., Pandolfi P.P. Does the ribosome translate cancer? Nat Rev Cancer. 2003;3:179–192. doi: 10.1038/nrc1015. [PubMed] [Cross Ref]
  • Saleh A., Srinivasula S.M., Balkir L., Robbins P.D., Alnemri E. S. Negative regulation of the Apaf-1 apoptosome by Hsp70. Nat Cell Biol. 2000;2:476–483. doi: 10.1038/35019510. [PubMed] [Cross Ref]
  • Salvesen G.S., Duckett C.S. IAP proteins: blocking the road to death’s door. Nat Rev Mol Cell Biol. 2002;3:401–410. doi: 10.1038/nrm830. [PubMed] [Cross Ref]
  • Saxena S.K., Sirdeshmukh R., Ardelt W., Mikulski S.M., Shogen K., Youle R.J. Entry into cells and selective degradation of tRNAs by a cytotoxic member of the RNase A family. J Biol Chem. 2002;277:15142–15146. doi: 10.1074/jbc.M108115200. [PubMed] [Cross Ref]
  • Schwickart M., Huang X., Lill J.R., Liu J., Ferrando R., French D. M., Maecker H., O’Rourke K., Bazan F., Eastham-Anderson J., et al. Deubiquitinase USP9X stabilizes MCL1 and promotes tumour cell survival. Nature. 2010;463:103–107. doi: 10.1038/nature08646. [PubMed] [Cross Ref]
  • Shaheen H.H., Horetsky R.L., Kimball S.R., Murthi A., Jefferson L. S., Hopper A.K. Retrograde nuclear accumulation of cytoplasmic tRNA in rat hepatoma cells in response to amino acid deprivation. Proc Natl Acad Sci U S A. 2007;104:8845–8850. doi: 10.1073/pnas.0700765104. [PubMed] [Cross Ref]
  • Soengas M.S., Capodieci P., Polsky D., Mora J., Esteller M., Opitz-Araya X., McCombie R., Herman J.G., Gerald W.L., Lazebnik Y. A., et al. Inactivation of the apoptosis effector Apaf-1 in malignant melanoma. Nature. 2001;409:207–211. doi: 10.1038/35051606. [PubMed] [Cross Ref]
  • Suhasini A.N., Sirdeshmukh R. Transfer RNA cleavages by onconase reveal unusual cleavage sites. J Biol Chem. 2006;281:12201–12209. doi: 10.1074/jbc.M504488200. [PubMed] [Cross Ref]
  • Thompson C.B. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267:1456–1462. doi: 10.1126/science.7878464. [PubMed] [Cross Ref]
  • Thompson D.M., Lu C., Green P.J., Parker R. tRNA cleavage is a conserved response to oxidative stress in eukaryotes. RNA. 2008;14:2095–2103. doi: 10.1261/rna.1232808. [PubMed] [Cross Ref]
  • Thompson D.M., Parker R. The RNase Rny1p cleaves tRNAs and promotes cell death during oxidative stress in Saccharomyces cerevisiae. J Cell Biol. 2009;185:43–50. doi: 10.1083/jcb.200811119. [PMC free article] [PubMed] [Cross Ref]
  • Thompson D.M., Parker R. Stressing out over tRNA cleavage. Cell. 2009;138:215–219. doi: 10.1016/j.cell.2009.07.001. [PubMed] [Cross Ref]
  • Vaughn A.E., Deshmukh M. Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome c. Nat Cell Biol. 2008;10:1477–1483. doi: 10.1038/ncb1807. [PMC free article] [PubMed] [Cross Ref]
  • Vaux D.L., Korsmeyer S.J. Cell death in development. Cell. 1999;96:245–254. doi: 10.1016/S0092-8674(00)80564-4. [PubMed] [Cross Ref]
  • Vousden K.H., Lane D.P. p53 in health and disease. Nat Rev Mol Cell Biol. 2007;8:275–283. doi: 10.1038/nrm2147. [PubMed] [Cross Ref]
  • Wallace D.C. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407. doi: 10.1146/annurev.genet.39.110304.095751. [PMC free article] [PubMed] [Cross Ref]
  • Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922–2933. [PubMed]
  • Watanabe Y., Kawai G., Yokogawa T., Hayashi N., Kumazawa Y., Ueda T., Nishikawa K., Hirao I., Miura K., Watanabe K. Higher-order structure of bovine mitochondrial tRNA (SerUGA): chemical modification and computer modeling. Nucleic Acids Res. 1994;22:5378–5384. doi: 10.1093/nar/22.24.5378. [PMC free article] [PubMed] [Cross Ref]
  • White R.J. RNA polymerase III transcription and cancer. Oncogene. 2004;23:3208–3216. doi: 10.1038/sj.onc.1207547. [PubMed] [Cross Ref]
  • White R.J. RNA polymerases I and III, growth control and cancer. Nat Rev Mol Cell Biol. 2005;6:69–78. doi: 10.1038/nrm1551. [PubMed] [Cross Ref]
  • Yamasaki S., Ivanov P., Hu G.F., Anderson P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J Cell Biol. 2009;185:35–42. doi: 10.1083/jcb.200811106. [PMC free article] [PubMed] [Cross Ref]
  • Yang X., Chang H.Y., Baltimore D. Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell. 1998;1:319–325. doi: 10.1016/S1097-2765(00)80032-5. [PubMed] [Cross Ref]
  • Yue D., Maizels N., Weiner A.M. CCA-adding enzymes and poly(A) polymerases are all members of the same nucleotidyltransferase superfamily: characterization of the CCA-adding enzyme from the archaeal hyperthermophile Sulfolobus shibatae. RNA. 1996;2:895–908. [PubMed]
  • Zou H., Henzel W.J., Liu X., Lutschg A., Wang X. Apaf-1, a human protein homologous to C. elegans CED-4, participates in cytochrome c-dependent activation of caspase-3. Cell. 1997;90:405–413. doi: 10.1016/S0092-8674(00)80501-2. [PubMed] [Cross Ref]

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