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Human Mitochondrial tRNA Processing (∗)

  • Walter Rossmanith
    Affiliations
    Institut für Tumorbiologie-Krebsforschung der Universität Wien, PG Genexpression, Borschkegasse 8a, 1090 Wien, Austria
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  • Apollonia Tullo
    Affiliations
    Centro di Studio sui Mitocondri e Metabolismo Energetico, CNR Bari, Via Amendola 165/A, 70126 Bari, Italy
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  • Thomas Potuschak
    Footnotes
    Affiliations
    Institut für Tumorbiologie-Krebsforschung der Universität Wien, PG Genexpression, Borschkegasse 8a, 1090 Wien, Austria
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  • Robert Karwan
    Correspondence
    To whom correspondence should be addressed. Tel.: 43-1-40154-240; Fax: 43-1-4060790
    Affiliations
    Institut für Tumorbiologie-Krebsforschung der Universität Wien, PG Genexpression, Borschkegasse 8a, 1090 Wien, Austria
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  • Elisabetta Sbis
    Affiliations
    Centro di Studio sui Mitocondri e Metabolismo Energetico, CNR Bari, Via Amendola 165/A, 70126 Bari, Italy
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  • Author Footnotes
    ∗ This work was supported in part by the Austrian Science Foundation and Austrian Ministry of Foreign Affairs, European Molecular Biology Organization (short-term fellowship ASTF 7159 (to A. T.)), Progetto Finalizzato Ingegneria Genetica (CNR Italy), and MURST (Italy). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
    § Present address: Institut für Botanik der Universität Wien, Abteilung für Zytologie und Genetik, Rennweg 14, 1030 Wien, Austria.
Open AccessPublished:May 26, 1995DOI:https://doi.org/10.1074/jbc.270.21.12885
      tRNA processing is a central event in mammalian mitochondrial gene expression. We have identified key enzymatic activities (ribonuclease P, precursor tRNA 3′-endonuclease, and ATP(CTP)-tRNA-specific nucleotidyltransferase) that are involved in HeLa cell mitochondrial tRNA maturation. Different mitochondrial tRNA precursors are cleaved precisely at the tRNA 5′- and 3′-ends in a homologous mitochondrial in vitro processing system. The cleavage at the 5′-end precedes that at the 3′-end, and the tRNAs are substrates for the specific CCA addition in the same in vitro system. Using a comparative enzymatic approach as well as biochemical and immunological techniques, we furthermore demonstrate that human cells contain two distinct enzymes that remove 5′-extensions from tRNA precursors, the previously characterized nuclear and the newly identified mitochondrial ribonuclease P. These two cellular isoenzymes have different substrate specificities that seem to be well adapted to their structurally disparate mitochondrial and nuclear tRNA substrates. This kind of approach may also help to understand the structural diversities and commonalities of tRNAs.

      INTRODUCTION

      Almost all RNA molecules are synthesized as immature precursors. Their conversion to functional species is a crucial step in gene expression. Contrasting with the diversity of RNA maturation processes of the various nuclear transcripts, RNA maturation in mammalian mitochondria is believed to involve only a handful of different steps (for recent review, see Refs.
      • Clayton D.A.
      ,
      • Attardi G.
      ,
      • Saccone C.
      • Sbis E.
      ). The 11 mRNAs, 2 rRNAs, and 22 tRNAs encoded in the circular mitochondrial genome originate from polycistronic primary transcripts. These do not contain introns nor do most of the mRNAs have flanking untranslated regions. The tRNA sequences “punctuate” the transcripts since they are immediately contiguous to the rRNA and protein-coding (mRNA) sequences and almost regularly interspersed between them. This unique genetic arrangement led to a model which predicted that the endonucleolytic processing of mitochondrial transcripts is carried out mainly by precursor (pre-)tRNA1(
      The abbreviations used are: pre-tRNA
      precursor tRNA
      RNase P
      ribonuclease P
      (mt)
      mitochondrial
      (n)
      nuclear
      pre-tRNATyrsu3+
      precursor suppressor III tRNATyr
      DTT
      dithiothreitol
      CIP
      calf intestinal alkaline phosphatase
      RNP(s)
      ribonucleoprotein(s)
      RNaseMRP
      ribonuclease mitochondrial RNA processing
      snRNA
      small nuclear RNA.
      ) processing enzymes cleaving precisely at the 5′- and 3′-ends of the tRNAs. In other words, RNA processing of polycistronic primary transcripts would lead to tRNAs, mRNAs, and rRNAs as a natural consequence of tRNA processing (
      • Ojala D.
      • Merkel C.
      • Gelfand R.
      • Attardi G.
      ,
      • Ojala D.
      • Montoya J.
      • Attardi G.
      ,
      • Anderson S.
      • Bankier A.T.
      • Barrell B.G.
      • de Bruijn M.H.L.
      • Coulson A.R.
      • Drouin J.
      • Eperon I.C.
      • Nierlich D.P.
      • Roe B.A.
      • Sanger F.
      • Schreier P.H.
      • Smith A.J.H.
      • Staden R.
      • Young I.G.
      ,
      • Montoya J.
      • Ojala D.
      • Attardi G.
      ). CCA addition, polyadenylation, and base modification of some nucleotides would then complete the maturation of the different RNA species. However, no mammalian mitochondrial tRNA processing enzyme (i.e. an enzyme from mitochondria capable of processing mitochondrial pre-tRNAs) has been found since the original proposal of this model in 1980/81 (discussed in Refs.
      • Clayton D.A.
      ,
      • Karwan R.
      ). Thus, testing the validity of the model by means of an in vitro processing system is a critical experiment and an indispensable need for the identification of mitochondrial tRNA processing enzymes.
      This work represents the first direct demonstration of animal mitochondrial activities involved in the processing of mitochondrial tRNAs using a homologous in vitro processing system. We report the precise 5′- and 3′-endonucleolytic processing of human mitochondrial tRNA precursors in HeLa cell mitochondrial extracts and the 3′-terminal CCA addition to these processed mitochondrial tRNAs. Furthermore, we demonstrate that human cells contain two distinct activities that remove 5′ leaders from pre-tRNAs (RNase P(s)). Their peculiar substrate specificities and the way they fractionate suggest strongly that the newly identified RNase P activity is mitochondrial whereas the other is nuclear, also indicating that previous mammalian RNase P isolations likely reflect the latter (
      • Koski R.A.
      • Bothwell A.L.M.
      • Altman S.
      ,
      • Gold H.A.
      • Craft J.
      • Hardin J.A.
      • Bartkiewicz M.
      • Altman S.
      ,
      • Bartkiewicz M.
      • Gold H.
      • Altman S.
      ,
      • Karwan R.
      • Bennett J.L.
      • Clayton D.A.
      ,
      • Doersen C.-J.
      • Guerrier-Takada C.
      • Altman S.
      • Attardi G.
      ,
      • Manam S.
      • Van Tuyle G.C.
      ).

      DISCUSSION

      Using a homologous cell-free in vitro system, we have identified three enzymatic activities involved in the biosynthesis of mammalian mitochondrial tRNAs. Highly purified HeLa cell mitochondria/mitoplasts contain 5′- and 3′-endonucleases and an ATP(CTP) nucleotidyltransferase activity; these specifically process human mitochondrial tRNA precursors to mature CCA containing tRNAs. Our results provide direct support for the tRNA punctuation model of mitochondrial RNA processing (
      • Ojala D.
      • Montoya J.
      • Attardi G.
      ). Moreover, the development of this first homologous animal mitochondrial in vitro processing system provides the basis for a future biochemical characterization of the enzymes involved as well as for an analysis of the role of tRNA processing in certain human mitochondrial diseases (
      • King M.P.
      • Koga Y.
      • Davidson M.
      • Schon E.A.
      ,
      • Bindoff L.A.
      • Howell N.
      • Poulton J.
      • McCullough D.A.
      • Morten K.J.
      • Lightowlers R.N.
      • Turnbull D.M.
      • Weber K.
      ,
      • Schon E.A.
      • Hirano M.
      • DiMauro S.
      ).
      The endonucleolytic activity that cofractionates with mitochondria and specifically cleaves human mitochondrial tRNA precursors at the predicted 5′-end of the tRNA should be termed mitochondrial RNase P for this reason (
      • Robertson H.D.
      • Altman S.
      • Smith J.D.
      ,
      • Altman S.
      • Kirsebom L.
      • Talbot S.
      ); the enzyme is analogous to all other known RNase P activities, with regard to its magnesium ion requirement as well as the generation of 5′-phosphate and 3′-hydroxyl termini at the site of cleavage, suggesting a possibly similar cleavage mechanism. Apart from these similarities, our data demonstrate that the identified mitochondrial RNase P is distinct from all previously described mammalian RNase P activities (
      • Koski R.A.
      • Bothwell A.L.M.
      • Altman S.
      ,
      • Gold H.A.
      • Craft J.
      • Hardin J.A.
      • Bartkiewicz M.
      • Altman S.
      ,
      • Bartkiewicz M.
      • Gold H.
      • Altman S.
      ,
      • Karwan R.
      • Bennett J.L.
      • Clayton D.A.
      ,
      • Doersen C.-J.
      • Guerrier-Takada C.
      • Altman S.
      • Attardi G.
      ,
      • Manam S.
      • Van Tuyle G.C.
      ). The mitochondrial RNase P described in this paper does, in particular, not correspond to RNase P activities previously purified from HeLa cell or rat liver mitochondria (
      • Doersen C.-J.
      • Guerrier-Takada C.
      • Altman S.
      • Attardi G.
      ,
      • Manam S.
      • Van Tuyle G.C.
      ), which were identified and characterized by their ability to cleave E. coli pre-tRNATyrsu3+ at the same site as E. coli RNase P. In contrast to these previous reports, the mitochondrial activity described herein does not cleave E. coli pre-tRNATyrsu3+ but cleaves authentic mammalian mitochondrial tRNA precursors and thereby fulfills the functional criterion for a mitochondrial RNase P not previously demonstrated for any other mammalian RNase P activity (for discussion, see Refs.
      • Clayton D.A.
      ,
      • Karwan R.
      ). Considering the cleavage potential of mitochondrial and nuclear RNase P described in this paper, those earlier preparations probably reflect the nuclear enzyme; indeed, this earlier RNase P activity was recently reported to copurify with an RNA identical to that of the nuclear RNase P (
      • Attardi G.
      ).
      This discrepancy to previous reports and the minute traces of H1 RNA found in extracts of rigorously defined mitochondrial fractions raise the question of whether there is a second mitochondrial RNase P species identical to the nuclear enzyme. In evaluating this possibility, it has to be considered that (i) the amount of mitoplast-associated H1 RNA is rather low and corresponds to that reported for other snRNAs,3(
      LoopDloop (Gilbert, D. G. (1992)), a Macintosh program for visualizing RNA secondary structure, is published electronically on the Internet and available via anonymous ftp to ftp.bio.indiana.edu.
      ) e.g. spliceosomal U snRNAs, estimated to be less than 1 molecule per 100 mitochondria (
      • Kiss T.
      • Filipowicz W.
      ); (ii) nuclear RNase P is not detectable as an activity in our mitochondrial in vitro system (probably due to its extremely low abundance, see (i)); (iii) all residual H1 RNA (and breakdown products thereof) is assembled as a Th/To RNP and thus most likely indeed represents nuclear RNase P. Considering that no bacterial, nucleocytoplasmic, or organellar genetic system has thus far been shown to contain two different RNase P enzymes, mammalian mitochondria would be the leading case of a partial RNase P redundancy.
      The finding that human cells contain two distinct RNase P enzymes led us to a comparative study of the HeLa cell RNase P isoenzymes. In other words, we have asked: what is the conserved capacity, in terms of substrate recognition and cleavage, of nuclear or mitochondrial RNase P, or which are the conserved features of nuclear or mitochondrial encoded tRNAs that make them substrates for one or the other? Interestingly, (mt)pre-tRNALeu(UUR) is a model substrate both for the nuclear as well as the mitochondrial enzyme. In contrast, (mt)pre-tRNATyr, which is efficiently cleaved by the mitochondrial enzyme, is not a substrate for nuclear RNase P. These results are consistent with the observation that (mt)tRNALeu(UUR) is the most conventional mitochondrial tRNA in the sense that it retains all the invariant and semi-invariant nucleotides conserved in nonorganellar tRNAs (
      • Anderson S.
      • Bankier A.T.
      • Barrell B.G.
      • de Bruijn M.H.L.
      • Coulson A.R.
      • Drouin J.
      • Eperon I.C.
      • Nierlich D.P.
      • Roe B.A.
      • Sanger F.
      • Schreier P.H.
      • Smith A.J.H.
      • Staden R.
      • Young I.G.
      ,
      • Kim S.H.
      • Suddath F.L.
      • Quigley G.J.
      • McPherson A.
      • Sussman J.L.
      • Wang A.H.J.
      • Seeman N.C.
      • Rich A.
      ,
      • Steinberg S.
      • Misch A.
      • Sprinzl M.
      ). Its tertiary structure may thus be assumed to be more similar to cytoplasmic or bacterial tRNAs than that of other mitochondrial tRNAs, e.g. (mt)tRNATyr, which lack one or more of these conserved features. In particular the D- and TψC-loops of many mitochondrial tRNAs deviate in length and base composition. The inability of mitochondrial RNase P to cleave (n)pre-tRNASer or E. coli pre-tRNATyrsu3+ (both of which are substrates for the nuclear enzyme) poses the question of what differentiates these tRNAs from (mt)tRNALeu(UUR). All three tRNAs have all the conserved features, and the only apparent difference is the length of the variable arm. Considering what is known about RNase P substrate recognition (reviewed in Ref.
      • Altman S.
      • Kirsebom L.
      • Talbot S.
      ), we cannot decide if the distinct but overlapping cleavage potential of mitochondrial and nuclear RNase P can be attributed to this structural variation. Nevertheless, our results make us confident that it is possible to study the structural diversities and commonalities of tRNAs as well as the coevolution of the two cellular RNase P enzymes with their in vivo substrates by a quantitative enzymatic study.
      The tRNA punctuation model of mitochondrial RNA processing (
      • Ojala D.
      • Montoya J.
      • Attardi G.
      ) implies that the tRNA 3′-ends and concomitantly the 5′-ends of rRNAs and mRNAs are formed by single endonucleolytic cuts. This contrasts with the best characterized mechanism of tRNA 3′-end formation in eubacteria, where exo- and endonucleases are required (
      • Deutscher M.P.
      ). Human mitochondrial tRNA precursors are cleaved precisely and endonucleolytically at the predicted 3′-end of the tRNA in our in vitro system. The 3′-CCA sequence is then added stepwise by an ATP(CTP)-tRNA-specific nucleotidyltransferase activity to the 3′-hydroxyl terminus. The endonucleolytic mode of mammalian mitochondrial tRNA 3′-end formation and the posttranscriptional CCA addition resemble the tRNA maturation mechanisms reported for organellar tRNAs of other organisms (
      • Chen J.-Y.
      • Martin N.C.
      ,
      • Hopper A.K.
      • Martin N.C.
      ,
      • Hanic-Joyce P.J.
      • Gray M.W.
      ,
      • Oommen A.
      • Li X.
      • Gegenheimer P.
      ). We have not yet attempted to separate the pre-tRNA 5′- and 3′-endonucleolytic activities found in HeLa cell mitochondria. However, considering that different enzymes act on the 5′- and 3′-ends of pre-tRNAs in other genetic systems, it is likely that also in human mitochondria 5′- and 3′-cleavages are carried out by distinct enzymes.
      The lack of a detectable processing intermediate corresponding to a (mt)pre-tRNA with processed tRNA 3′-end but unprocessed 5′-end suggests an ordered pathway of processing of mitochondrial tRNAs in vitro, with 5′-cleavage preceding 3′-cleavage. Biochemical separation of the mitochondrial pre-tRNA 3′-endonuclease activity from RNase P will be necessary to determine if the 3′-cleavage strictly depends on a 5′-processed substrate. Even this would not necessarily imply an obligatory order of cleavages in vivo, and in fact a tRNA processed at its 3′-end but not at the 5′-end, most likely representing a processing intermediate, has been observed in rat mitochondria (
      • Sbis E.
      • Tullo A.
      • Nardelli M.
      • Tanzariello F.
      • Saccone C.
      ). Similar observations have been made for yeast mitochondrial tRNA processing; while in vitro the action of a 3′-endonuclease appears to depend on a 5′-matured pre-tRNA substrate (
      • Chen J.-Y.
      • Martin N.C.
      ), petite mutants of Saccharomyces cerevisiae containing mitochondrial tRNA genes but lacking the mitochondrial RNase P RNA locus accumulate mitochondrial tRNA precursors with 5′-extensions and mature 3′ termini (
      • Frontali L.
      • Palleschi C.
      • Francisci S.
      ,
      • Palleschi C.
      • Francisci S.
      • Zennaro E.
      • Frontali L.
      ,
      • Martin N.C.
      • Miller D.L.
      • Underbrink K.
      • Ming X.
      ). Taken together, these observations suggest that the cellular route to mature mitochondrial tRNAs is not rigidly fixed.
      While resecting tRNAs from primary transcripts obviously accounts for the majority of mammalian mitochondrial RNA processing, some mitochondrial RNA termini cannot be explained by tRNA processing; these are the 5′-ends of the cytochrome oxidase subunit 1 and 3 mRNAs and of the cytochrome b mRNA, respectively, the 3′-ends of the ATPase subunit 6 mRNA and the NADH dehydrogenase subunit 5 mRNA (
      • Ojala D.
      • Merkel C.
      • Gelfand R.
      • Attardi G.
      ,
      • Ojala D.
      • Montoya J.
      • Attardi G.
      ,
      • Montoya J.
      • Ojala D.
      • Attardi G.
      ,
      • Nardelli M.
      • Tommasi S.
      • D'Erchia A.M.
      • Tanzariello F.
      • Tullo A.
      • Primavera A.T.
      • De Lena M.
      • Sbis E.
      • Saccone C.
      ), as well as the different displacement loop RNA species believed to arise from RNA processing of light strand transcripts in this region (reviewed in Ref.
      • Clayton D.A.
      ). It is tempting to speculate that one of the activities described here processes these potential substrates, in analogy to E. coli RNase P, which cleaves the precursor to 4.5 S RNA in addition to pre-tRNAs (
      • Guerrier-Takada C.
      • Gardiner K.
      • Marsh T.
      • Pace N.
      • Altman S.
      ). Careful in vitro analysis will be necessary to answer these questions.

      Acknowledgments

      We thank P. Breit for help with the figure preparation, D. A. Clayton for pUC19pSer, R. Lührmann for antisera, N. C. Martin for helpful advice, M. Nardelli for help in subcloning phL, C. Saccone for helpful advice, W. J. van Venrooij for antisera, V. Wintersberger for helpful advice, and the Dept. of Molecular Genetics (this institute) for instrumental equipment and support.

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