The role of specialized ribosomes in stress resistance and healthy aging

• Applicant: Martin Kos, Ph.D.
• Subject Area: Biogerontology and Geriatric Medicine ; Biochemistry
• Term: from 2016 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 280594475

• Final Report Year: 2019

Final Report Abstract

In summary, we have successfully identified differentially modified ribosomes in the senescent and quiescent cells. We could show that snoRNAs responsible for the altered modification are also differentially expressed. In the WP5 we identified about 10,000 rancRNAs associated with ribosomes in human cells and their functional analysis is ongoing. Furthermore, we characterized the effect of the lack of the rRNA methyltransferases NSUN-5, NOL-2 and RRP-8 on the development, growth, behavior and viability of the nematode C. elegans. In addition, we showed that ribosome biogenesis switches between two alternative pathways in both yeast and human, providing a plausible mechanism to produce different ribosomes. The research initiated in this project continues. The work provides a proof of principle that distinct ribosomes are produced in senescent cells. If the currently planned experiments confirm a functional relevance of the modifications for the establishment or maintenance of senescence or quiescence, then the methylation sites we identified here, the relevant snoRNAs and their host genes will represent potential targets for drugs modulating not only the ageing process, but also for treatments of proliferative diseases.

Publications

• (2019) Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth. Nucleic acids research 47 (22) 11807–11825
  Heissenberger, Clemens; Liendl, Lisa; Nagelreiter, Fabian; Gonskikh, Yulia; Yang, Guohuan; Stelzer, Elena M.; Krammer, Teresa L.; Micutkova, Lucia; Vogt, Stefan; Kreil, David P.; Sekot, Gerhard; Siena, Emilio; Poser, Ina; Harreither, Eva; Linder, Angela;
  
• (2017). Alterations of the translation apparatus during aging and stress response. Mech. Ageing Dev. S0047-6374(16)30221-4
  Gonskikh Y. and Polacek N.
  
• (2017). Post-transcriptional regulation of ribosome biogenesis in yeast. Microbial Cell 4, 179
  Kos-Braun, I.C., and Koš, M.
  
• (2017). Tor1 and CK2 kinases control a switch between alternative ribosome biogenesis pathways in a growth-dependent manner. PLoS Biology 15, e2000245
  Kos-Braun, I.C., Jung, I., and Koš, M.
  
• Blocking negative effects of senescence in human skin fibroblasts with a plant extract, NPJ Aging Mech Dis 2018
  Lämmermann I, Terlecki-Zaniewicz L, Weinmüllner R, Schosserer M, Dellago H, Dargen de Matos Branco A, Autheried D, Sevcnikar D, Kleissl L, Berlin I, Morizot F, Lejeune F, Fuzzati N, Forestier S, Toribio A, Tromeur A, Weinberg L, Higareda Almaraz JC , Scheideler M , Rietveld M, El Ghalbzouri A, Tschachler E, Gruber F and Grillari J
  
• Extracellular vesicles and their miRNA cargo are anti-apoptotic members of the SASP, Aging 2018
  Terlecki-Zaniewicz L, Lämmermann I, Latreille J, Bobbili MR, Pils V, Schosserer M, Weinmüllner R, Dellago H, Skalicky S, Pum D, Higareda Almaraz JC, Scheideler M, Morizot F, Hackl M, Gruber F, Grillari J
  
• OPP labelling enables total protein synthesis quantification in CHO production cell lines at the singlecell level. Biotechnol J. 2018
  Nagelreiter, F; Coats, M; Klanert, G; Gludovacz, E; Borth, N; Grillari, J; Schosserer, M
  
• (2019). A ribosome assembly stress response regulates transcription to maintain proteome homeostasis
  Albert, B., Kos-Braun, I.C., Henras, A.K., Dez, C., Rueda, M.P., Zhang, X., Gadal, O., Kos, M., and Shore, D.