CLP1 links tRNA metabolism to progressive motor-neuron loss (original) (raw)

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

Data have been deposited in the Gene Expression Omnibus under accession numbers GSE35924 and GSE39275.

References

1. Weitzer, S. & Martinez, J. The human RNA kinase hClp1 is active on 3′ transfer RNA exons and short interfering RNAs. Nature 447, 222–226 (2007)
   Article ADS CAS PubMed Google Scholar
2. Ramirez, A., Shuman, S. & Schwer, B. Human RNA 5′-kinase (hClp1) can function as a tRNA splicing enzyme in vivo . RNA 14, 1737–1745 (2008)
   Article CAS PubMed PubMed Central Google Scholar
3. Jain, R. & Shuman, S. Characterization of a thermostable archaeal polynucleotide kinase homologous to human Clp1. RNA 15, 923–931 (2009)
   Article CAS PubMed PubMed Central Google Scholar
4. de Vries, H. et al. Human pre-mRNA cleavage factor IIm contains homologs of yeast proteins and bridges two other cleavage factors. EMBO J. 19, 5895–5904 (2000)
   Article CAS PubMed PubMed Central Google Scholar
5. Minvielle-Sebastia, L., Preker, P. J., Wiederkehr, T., Strahm, Y. & Keller, W. The major yeast poly(A)-binding protein is associated with cleavage factor IA and functions in premessenger RNA 3′-end formation. Proc. Natl Acad. Sci. USA 94, 7897–7902 (1997)
   Article ADS CAS PubMed Google Scholar
6. Holbein, S. et al. The P-loop domain of yeast Clp1 mediates interactions between CF IA and CPF factors in pre-mRNA 3′ end formation. PLoS ONE 6, e29139 (2011)
   Article ADS CAS PubMed PubMed Central Google Scholar
7. Haddad, R. et al. An essential role for Clp1 in assembly of polyadenylation complex CF IA and Pol II transcription termination. Nucleic Acids Res. 40, 1226–1239 (2012)
   Article CAS PubMed Google Scholar
8. Ghazy, M. A. et al. The interaction of Pcf11 and Clp1 is needed for mRNA 3′-end formation and is modulated by amino acids in the ATP-binding site. Nucleic Acids Res. 40, 1214–1225 (2012)
   Article ADS CAS PubMed Google Scholar
9. Paushkin, S. V., Patel, M., Furia, B. S., Peltz, S. W. & Trotta, C. R. Identification of a human endonuclease complex reveals a link between tRNA splicing and pre-mRNA 3′ end formation. Cell 117, 311–321 (2004)
   Article CAS PubMed Google Scholar
10. Trotta, C. R. et al. The yeast tRNA splicing endonuclease: a tetrameric enzyme with two active site subunits homologous to the archaeal tRNA endonucleases. Cell 89, 849–858 (1997)
    Article CAS PubMed Google Scholar
11. Zillmann, M., Gorovsky, M. A. & Phizicky, E. M. Conserved mechanism of tRNA splicing in eukaryotes. Mol. Cell. Biol. 11, 5410–5416 (1991)
    Article CAS PubMed PubMed Central Google Scholar
12. Zhao, C. et al. Charcot-Marie-Tooth disease type 2A caused by mutation in a microtubule motor KIF1Bβ. Cell 105, 587–597 (2001)
    Article CAS PubMed Google Scholar
13. Sánchez-Carbente, M. R., Castro-Obregon, S., Covarrubias, L. & Narvaez, V. Motoneuronal death during spinal cord development is mediated by oxidative stress. Cell Death Differ. 12, 279–291 (2005)
    Article PubMed Google Scholar
14. Medana, I. M. & Esiri, M. M. Axonal damage: a key predictor of outcome in human CNS diseases. Brain 126, 515–530 (2003)
    Article CAS PubMed Google Scholar
15. Atkin, J. D. et al. Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis. Neuromuscul. Disord. 15, 377–388 (2005)
    Article PubMed Google Scholar
16. Yamasaki, S., Ivanov, P., Hu, G. F. & Anderson, P. Angiogenin cleaves tRNA and promotes stress-induced translational repression. J. Cell Biol. 185, 35–42 (2009)
    Article CAS PubMed PubMed Central Google Scholar
17. Ivanov, P., Emara, M. M., Villen, J., Gygi, S. P. & Anderson, P. Angiogenin-induced tRNA fragments inhibit translation initiation. Mol. Cell 43, 613–623 (2011)
    Article CAS PubMed PubMed Central Google Scholar
18. Son, E. Y. et al. Conversion of mouse and human fibroblasts into functional spinal motor neurons. Cell Stem Cell 9, 205–218 (2011)
    Article CAS PubMed PubMed Central Google Scholar
19. Lambert, P. F., Kashanchi, F., Radonovich, M. F., Shiekhattar, R. & Brady, J. N. Phosphorylation of p53 serine 15 increases interaction with CBP. J. Biol. Chem. 273, 33048–33053 (1998)
    Article CAS PubMed Google Scholar
20. Dumaz, N. & Meek, D. W. Serine 15 phosphorylation stimulates p53 transactivation but does not directly influence interaction with HDM2. EMBO J. 18, 7002–7010 (1999)
    Article CAS PubMed PubMed Central Google Scholar
21. Chao, C. et al. Cell type- and promoter-specific roles of Ser18 phosphorylation in regulating p53 responses. J. Biol. Chem. 278, 41028–41033 (2003)
    Article CAS PubMed Google Scholar
22. Arber, S. et al. Requirement for the homeobox gene Hb9 in the consolidation of motor neuron identity. Neuron 23, 659–674 (1999)
    Article CAS PubMed Google Scholar
23. Hanada, R. et al. Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nature Med. 10, 1067–1073 (2004)
    Article CAS PubMed Google Scholar
24. Tuck, A. C. & Tollervey, D. RNA in pieces. Trends Genet. 27, 422–432 (2011)
    Article CAS PubMed Google Scholar
25. Hurto, R. L. Unexpected functions of tRNA and tRNA processing enzymes. Adv. Exp. Med. Biol. 722, 137–155 (2011)
    Article CAS PubMed Google Scholar
26. Lee, Y. S., Shibata, Y., Malhotra, A. & Dutta, A. A novel class of small RNAs: tRNA-derived RNA fragments (tRFs). Genes Dev. 23, 2639–2649 (2009)
    Article CAS PubMed PubMed Central Google Scholar
27. Herbst, R., Iskratsch, T., Unger, E. & Bittner, R. E. Aberrant development of neuromuscular junctions in glycosylation-defective Large myd mice. Neuromuscul. Disord. 19, 366–378 (2009)
    Article PubMed PubMed Central Google Scholar

Download references

Acknowledgements

We thank A. Meixner, M. Foong, T. Nakashima, H. C. Theussl, J. R. Wojciechowski, A. Bichl, the mouse pathology unit of the Universitätsklinikum Hamburg-Eppendorf, and G. P. Resch for discussions and technical support. We also thank T. Buerckstuemmer for providing the pRV-NTAP vector. J.M.P. is supported by grants from the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), the Austrian Ministry of Sciences, the Austrian Academy of Sciences, AustroMouse network of Genome Research in Austria (GEN-AU), Apoptosis systems biology applied to cancer and AIDS (ApoSys) and a European Research Council Advanced Grant from the European Union. J.M., S.W. and B.M. are supported by IMBA and GEN-AU (AustroMouse). T.H. is supported by the Japan Society for the Promotion of Science and the Astellas Foundation. J.K.I. was supported by National Institutes of Health (NIH) grant K99NS077435-01A1. M.G. is supported by grants from the German Research Foundation (DFG) (FG885 and GRK 1459), the Landesexzellenzinitiative Hamburg (Neurodapt). R.H. was supported by the Austrian Science Fund (P19223, P21667). C.J.W. is supported by the NIH (NS038253).

Author information

Author notes

1. Toshikatsu Hanada and Stefan Weitzer: These authors contributed equally to this work.

Authors and Affiliations

1. IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria ,
   Toshikatsu Hanada, Stefan Weitzer, Barbara Mair, Reiko Hanada, Michael Orthofer, Vukoslav Komnenovic, Javier Martinez & Josef M. Penninger
2. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, Hamburg 20246, Germany ,
   Christian Bernreuther & Markus Glatzel
3. Program in Neurobiology and F. M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, 02115, Massachusetts, USA
   Brian J. Wainger, Shane J. Cronin & Clifford J. Woolf
4. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, 02114, Massachusetts, USA
   Brian J. Wainger
5. Department of Stem Cell and Regenerative Biology, Howard Hughes Medical Institute, Harvard Stem Cell Institute. Boston, 02115, Massachusetts, USA
   Justin Ichida & Kevin C. Eggan
6. Department of Biological Chemistry. The Weizmann Institute of Science, Rehovot 76100, Israel,
   Adi Minis & Avraham Yaron
7. Department of Urology, Oita University Faculty of Medicine, 1-1 Idaigaoka, Hasama-machi, Yufu, Oita 879-5593, Japan,
   Fuminori Sato & Hiromitsu Mimata
8. Department of Microbiology and Immunology, Keio University School of Medicine, Shinjuku-ku, Tokyo 160-8582, Japan,
   Akihiko Yoshimura
9. Campus Science Support Facilities GmbH, Dr. Bohr-Gasse 3, Vienna 1030, Austria ,
   Ido Tamir
10. Division Molecular Pathophysiology, Biocenter, Medical University of Innsbruck, Innsbruck 6020, Austria,
    Johannes Rainer & Reinhard Kofler
11. Department of Neurobiology, Harvard Medical School, Boston, 02115, Massachusetts, USA
    Clifford J. Woolf
12. Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna 1090, Austria ,
    Ruth Herbst

Authors

1. Toshikatsu Hanada
   You can also search for this author inPubMed Google Scholar
2. Stefan Weitzer
   You can also search for this author inPubMed Google Scholar
3. Barbara Mair
   You can also search for this author inPubMed Google Scholar
4. Christian Bernreuther
   You can also search for this author inPubMed Google Scholar
5. Brian J. Wainger
   You can also search for this author inPubMed Google Scholar
6. Justin Ichida
   You can also search for this author inPubMed Google Scholar
7. Reiko Hanada
   You can also search for this author inPubMed Google Scholar
8. Michael Orthofer
   You can also search for this author inPubMed Google Scholar
9. Shane J. Cronin
   You can also search for this author inPubMed Google Scholar
10. Vukoslav Komnenovic
    You can also search for this author inPubMed Google Scholar
11. Adi Minis
    You can also search for this author inPubMed Google Scholar
12. Fuminori Sato
    You can also search for this author inPubMed Google Scholar
13. Hiromitsu Mimata
    You can also search for this author inPubMed Google Scholar
14. Akihiko Yoshimura
    You can also search for this author inPubMed Google Scholar
15. Ido Tamir
    You can also search for this author inPubMed Google Scholar
16. Johannes Rainer
    You can also search for this author inPubMed Google Scholar
17. Reinhard Kofler
    You can also search for this author inPubMed Google Scholar
18. Avraham Yaron
    You can also search for this author inPubMed Google Scholar
19. Kevin C. Eggan
    You can also search for this author inPubMed Google Scholar
20. Clifford J. Woolf
    You can also search for this author inPubMed Google Scholar
21. Markus Glatzel
    You can also search for this author inPubMed Google Scholar
22. Ruth Herbst
    You can also search for this author inPubMed Google Scholar
23. Javier Martinez
    You can also search for this author inPubMed Google Scholar
24. Josef M. Penninger
    You can also search for this author inPubMed Google Scholar

Contributions

T.H. generated mutant mice, performed mouse phenotyping and developed cell lines with help from R.H. S.W. and B.M. performed all biochemical assays and northern blots. V.K. performed histological analysis. F.S., H.M., S.J.C. and A.Y. provided key reagents and technical help for generation of mutant mice. I.T. analysed tRNA fragment distributions. M.O. performed calorimetric experiments. B.J.W., J.I., K.C.E. and C.J.W. performed and helped with transdifferentiation experiments and patch clamping. R.H. performed immunostainings and assessment of NMJs and motor-neuron pathfinding. A.M. and A.Y. performed DRG explant cultures, and J.R. and R.K. carried out exon arrays. C.B. and M.G. performed histological and immunohistochemical staining of, and assessed, peripheral nerve and brain structures. J.M. and J.M.P. coordinated the project and wrote the manuscript.

Corresponding authors

Correspondence toJavier Martinez or Josef M. Penninger.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

PowerPoint slides

Rights and permissions

About this article

Cite this article

Hanada, T., Weitzer, S., Mair, B. et al. CLP1 links tRNA metabolism to progressive motor-neuron loss.Nature 495, 474–480 (2013). https://doi.org/10.1038/nature11923

Download citation

• Received: 06 March 2012
• Accepted: 18 January 2013
• Published: 10 March 2013
• Issue Date: 28 March 2013
• DOI: https://doi.org/10.1038/nature11923