MARTIN KOŠ

Ribosomal RNA processing and modification

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RIBOSOME BIOGENESIS IN CELL GROWTH, DISEASE AND AGEING

Ribosome biogenesis is an essential major metabolic process in all organisms. The making of ribosomes in eukaryotes requires the coordinated action of all three RNA polymerases, numerous small nucleolar RNAs (snoRNAs) and several hundred protein factors. The highly dynamic and complex pathway of ribosome synthesis is directly or indirectly linked to various celullar processes.

As a high energy demanding process ribosome biogenesis is tightly controlled with respect to the cell growth. A dysregulation of ribosome biogenesis leads to surprisingly tissue-specific diseases and developmental defects. An upregulation of ribosome synthesis is a hallmark of most cancers and consequently the nucleolus and ribosome biogenesis are currently recognized as important targets for cancer therapy. Intriguingly, dysregulation of ribosome synthesis or translation also affects longevity and ageing.

The goal of the lab is to extend our understanding of molecular mechanism underlying the ribosome biogenesis and its regulation in healthy and pathological situations. We are interested in the following aspects of ribosome biogenesis:

Regulation of ribosome synthesis; nucleolar stress and usage of alternative pathways in development and disease.

The Tor signaling pathway controls ribosome biogenesis at different levels. While the control of transcription by Tor pathways is mechanistically fairly well understood, the regulation of pre-rRNA processing and assembly at the post-transcriptional level remains largely unexplored. We showed that yeast switches rapidly between two alternative pre-rRNA processing pathways in response to stress or nutrients availability. We aim to understand the regulation of the usage of alternative ribosome biogenesis pathways in mammals during development and cell differentiation as well as in pathophysiological situations, such as cancer.

Role of RNA modifications and snoRNAs.

The mature rRNAs are extensively covalently modified at >100 sites. The most numerous rRNA modifications are 2’-O-ribose methylation and pseudouridylation, which are guided by snoRNAs. In addition, many nucleotides in rRNAs are modified by specialized enzymes. While it is well accepted that the modifications contribute to the rRNA conformation and ribosome function, the roles of individual or clusters of modifications is not fully understood. Significantly, mutations in modifying enzymes have been linked to human diseases, e.g. dyskeratosis congenita or the Bowen-Conradi syndrome. Furthermore, a lack of certain modifications was shown to extend life-span of multiple organisms. We are investigating the molecular mechanisms by which the RNA modifications and snoRNAs exert their effect on the ribosome biogenesis and subsequently ribosome function.

Specialized ribosomes – formation and function? Role in ageing?

In the recent years it has become clear that ribosomes with differently modified rRNA or diverse protein composition coexist in cells. It has been proposed that these distinct ribosomes might be specialized for translation of a subset of mRNAs. We want to answer the following critical questions: Is the formation of different ribosomes regulated or is it a consequence (“side effect”) of the complex process of ribosome assembly with many steps occurring presumably stochastically? Do these different ribosomes have specific functions? With our colleagues we have recently reported that expression of the cytosine specific methyltransferase Rcm1/NSUN5 is reduced in stressed cells and during senescence. Importantly, deletion of Rcm1/NSUN5 increases the life-span and oxidative stress resistance. We therefore use aged and induced senescent cells as one of the model systems to investigate the role of differently modified ribosomes.

Download BZH Report Kos 2014-2016

Academic Training and Positions

1992 – 1997	Study of molecular genetics at the Charles University of Prague
1998 – 2002	PhD at the European Molecular Biology Laboratory (EMBL) Heidelberg and the Charles University of Prague
2002 - 2008	Postdoc at the Wellcome Trust Centre for Cell Biology, University of Edinburgh
August 2008 -	Junior group leader, Excellence Cluster “Cell Networks” at Heidelberg University Biochemistry Center (BZH)

ResearcherID E-2534-2011

2020
Yang,G., Heisenberger,C., Polacek,N., Grillari,J., Schosserer,M. and Koš,M. (2020). Cellular senescence and quiescence are associated with altered ribosomal RNA methylation and processing. BioRxiv doi: 10.1101/2020.04.01.019653.

Gonskikh,Y., Gerstl,M., Koš,M., Borth,N., Schosserer,M., Grillari,J. and Polacek,N. (2020). Modulation of mammalian translation by a ribosome associated tRNA half. RNA Biol 30:1-12,
doi: 10.1080/15476286.2020.1744296.

2019
Heisenberger, C., Liendl, L., Nagelreiter, F., Gonskikh, Y., Yang, G.,..., Koš, M., Polacek, N., Grillari, J., Schosserer, M. (2019). Loss of the ribosomal RNA methyltransferase NSUN5 impairs global protein synthesis and normal growth. Nucl Acids Res 47(22):11807-11825. doi: 10.1093/nar/gkz1043

Gnanasundram,S.V., Kos-Braun,I.C. and Koš,M. (2019). At least two molecules of the RNA helicase Has1 are simultaneously present in pre-ribosomes during ribosome biogenesis. Nucl Acids Res pii: gkz767. doi: 10.1093/nar/gkz767

Albert, B., Kos-Braun, I.C., Henras, A.K., Dez, C., Rueda, M.P., Zhang, X., Gadal, O., Kos, M., and Shore, D. (2019). A ribosome assembly stress response regulates transcription to maintain proteome homeostasis. eLife 2019;8:e45002 doi: 10.7554/eLife.45002

2017
Kos-Braun,I.C. and Koš,M. (2017). Post-transcriptional regulation of ribosome biogenesis in yeast. Microbial Cell 4(5): 179-181. doi: 10.15698/mic2017.05.575 (invited microreview)

Kos-Braun,I.C., Jung,I. and Koš,M. (2017). Tor1 and CK2 kinases control a switch between alternative ribosome biogenesis pathways in a growth dependent manner. PLoS Biol 15(3):e2000245. doi:10.1371/journal.pbio.2000245.

Heissenberger,C., Dimitrijevic,N., Gonskikh,Y., Linder,A., Grillari-Voglauer,R., Koš,M., Polacek,N., Grillari,J. and Schosserer,M. (2017). NSUN5 methylates ribosomal RNA and modulates ribosome function in human cells. Experimental Gerontology 94:115-116.

2016
Kornprobst,M., Turk,M., Kellner,N., Cheng,J., Flemming,D., Koš-Braun,I.C., Koš,M., Thoms,M., Berninghausen,O., Beckmann,R., Hurt,E., 2016. Architecture of the 90S Pre-ribosome: A Structural View on the Birth of the Eukaryotic Ribosome. Cell 166, 380–393.

Theile,D. and Koš,M. (2016). Structural and functional evaluation of interaction between mammalian ribosomal RNA with platinum-containing antineoplastic drugs. Toxicology Letters 242, 47-52.

2015
Boon,K.-L., Pearson,M.D. and Koš,M. (2015). Self-association of Trimethylguanosine Synthase Tgs1 is required for efficient snRNA/snoRNA trimethylation and pre-rRNA processing. Sci Rep 5, 11282.

Gnanasundram,S.V. and Koš,M. (2015). Fast protein depletion system utilizing tetracycline repressible promoter and N-end rule in yeast. Mol Biol Cell 26, 762-8.

Schosserer,M., Minois,N., Angerer,T.B., Amring,M., Dellago,H, Harreither,E., Calle-Perez,A., Pircher,A., Gerstl,M.P., Pfeifenberger,S., Brandl,C., Sonntagbauer,M., Kriegner,A., Linder,A., Weinhäusel,A., Mohr,T., Steiger,M., Mattanovich,D., Rinnerthaler,M., Karl,T., Sharma,S., Entian,K.-D., Koš,M., Breitenbach,M., Wilson,I.B.H., Polacek,N., Grillari-Voglauer,R., Breitenbach-Koller,L. and Grillari,J. (2015). Methylation of ribosomal RNA by Nsun5 is a conserved mechanism modulating organismal life span. Nat Commun 6, 6158.

2014
Bock,T., Chen,W.-H., Ori,A., Malik,N., Silva-Martin,N., Huerta-Cepas,J., Powell,S., Kastritis,P., Smyshlyaev,G., Vonkova,I., Kirkpatrick,J., Doerks,T., Nesme,L., Bassler,J., Koš,M., Hurt,E., Carlomagno,T., Gavin,A.-C., Barabás,O., Mueller,C., van Noort,V., Beck,M. and Bork,P. (2014). An integrated approach for genome annotation of the eukaryotic thermophile Chaetomium thermophilum. Nucl Acids Res 42, 13525-33.

Gigova A, Duggimpudi S, Pollex T, Schaefer M, Koš M. (2014). A cluster of methylations in the domain IV of 25S rRNA is required for ribosome stability. RNA 20, 1632-44.

2010
Alexander, R.D., Barrass, J.D., Dichtl,B., Koš,M., Obtulowicz,T., Robert,M.-C., Koper,M., Karkusiewicz,I., Mariconti,L., Tollervey,D., Dichtl,B., Kufel,J., Bertrand,E. and Beggs,J.D. (2010). RiboSys, a high-resolution, quantitative approach to measure the in vivo kinetics of pre-mRNA splicing and 3’-end processing in Saccharomyces cerevisiae. RNA 16, 2570-80.

Boon,K.-L. and Koš,M. (2010). Deletion of Swm2p selectively impairs trimethylation of snRNAs by Trimethylguanosine synthase (Tgs1p). FEBS Lett. 584, 3299-3304.

Koš,M. and Tollervey,D. (2010). Yeast Pre-rRNA Processing and Modification Occur Cotranscriptionally. Mol. Cell 37, 809-820.

2008
Bohnsack, M.T., Koš,M. and Tollervey,D. (2008). Quantitative analysis of snoRNA association with pre-ribosomes and release of snR30 by Rok1 helicase. EMBO Rep. 9, 1230-1236.

2007
Ciocchetta,F., Hillston,J., Koš,M. and Tollervey,D. (2007). Modelling yeast pre-rRNA processing. In the Proceedings of Computational Methods in Systems Biology (CMSB), 2007. To appear in LNBI, Springer.

2006
Belaya,K., Tollervey,D., and Koš,M. (2006). FLIPing heterokaryons to analyse nucleo-cytoplasmic shuttling of yeast proteins. RNA 12, 921-30.

2005
Koš,M. and Tollervey,D. (2005). The Putative RNA Helicase Dbp4p Is Required for Release of the U14 snoRNA from Preribosomes in Saccharomyces cerevisiae. Mol. Cell 20, 53-64.

2004
Metivier,R., Penot,G., Carmouche,R.P., Hubner,M.R., Reid,G., Denger,S., Manu,D., Brand,H., Koš,M., Benes,V. and others (2004). Transcriptional complexes engaged by apo-estrogen receptor-alpha isoforms have divergent outcomes. EMBO J. 23, 3653-3666.

2003
Metivier,R., Penot,G., Hubner,M.R., Reid,G., Brand,H., Koš,M., and Gannon,F. (2003). Estrogen receptor-alpha directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115, 751-763.

2002
Metivier,R., Stark,A., Flouriot,G., Hubner,M.R., Brand,H., Penot,G., Manu,D., Denger,S., Reid,G., Koš,M. and others (2002). A dynamic structural model for estrogen receptor-alpha activation by ligands, emphasizing the role of interactions between distant A and E domains. Mol. Cell 10, 1019-1032.

Reid,G., Denger,S., Koš,M., and Gannon,F. (2002). Human estrogen receptor-alpha: regulation by synthesis, modification and degradation. Cell Mol. Life Sci. 59, 821-831.

Koš,M., Denger,S., Reid,G., and Gannon,F. (2002). Upstream open reading frames regulate the translation of the multiple mRNA variants of the estrogen receptor alpha. J. Biol. Chem. 277, 37131-37138.

Koš,M., Denger,S., Reid,G., Korach,K.S., and Gannon,F. (2002). Down but not out? A novel protein isoform of the estrogen receptor alpha is expressed in the estrogen receptor alpha knockout mouse. J. Mol. Endocrinol. 29, 281-286.

Brand,H., Koš,M., Denger,S., Flouriot,G., Gromoll,J., Gannon,F., and Reid,G. (2002). A Novel Promoter Is Involved in the Expression of Estrogen Receptor alpha in Human Testis and Epididymis. Endocrinology 143, 3397-3404.

2001
Koš,M., Reid,G., Denger,S., and Gannon,F. (2001). Minireview: genomic organization of the human ERalpha gene promoter region. Mol. Endocrinol. 15, 2057-2063.

Denger,S., Reid,G., Brand,H., Koš,M., and Gannon,F. (2001). Tissue-specific expression of human ERalpha and ERbeta in the male. Mol. Cell Endocrinol. 178, 155-160.

Denger,S., Reid,G., Koš,M., Flouriot,G., Parsch,D., Brand,H., Korach,K.S., Sonntag-Buck,V., and Gannon,F. (2001). ERalpha gene expression in human primary osteoblasts: evidence for the expression of two receptor proteins. Mol. Endocrinol. 15, 2064-2077.

2000
Koš,M., O'Brien,S., Flouriot,G. and Gannon,F. (2000). Tissue-specific expression of multiple mRNA variants of the mouse estrogen receptor alpha gene. FEBS Lett. 477,15-20.

Flouriot,G., Brand,H., Denger,S., Metivier,R., Koš,M., Reid,G., Sonntag-Buck,V., and Gannon,F. (2000). Identification of a new isoform of the human estrogen receptor-alpha (hER-alpha) that is encoded by distinct transcripts and that is able to repress hER-alpha activation function 1. EMBO J. 19, 4688-4700.

1999
Kučerová,D., Šloncová,E., Tuháčková,Z., Uhlířová,M., Koš,M., and Sovová,V. (1999). Changes of E-cadherin and beta-catenin levels during induced differentiation of colorectal carcinoma cells. Int. J. Mol. Med. 4, 541-544

Contact

Heidelberg University
Biochemistry Center (BZH)
Im Neuenheimer Feld 328
69120 Heidelberg

E-Mail:

martin.kos.bzh@gmail.com

Groupleader: Martin Koš

Martin Koš

Ribosomal RNA processing and modification

Research

1.

2.

3.

4.

5.

RIBOSOME BIOGENESIS IN CELL GROWTH, DISEASE AND AGEING

Role of RNA modifications and snoRNAs.

Specialized ribosomes – formation and function? Role in ageing?

CV

Publications

Open Positions

Contact

Groupleader: Martin Koš

Martin Koš

Ribosomal RNA processing and modification

Research

1. 2. 3. 4. 5. RIBOSOME BIOGENESIS IN CELL GROWTH, DISEASE AND AGEING

Role of RNA modifications and snoRNAs.

Specialized ribosomes – formation and function? Role in ageing?

CV

Publications

Open Positions

Contact

1.

2.

3.

4.

5.

RIBOSOME BIOGENESIS IN CELL GROWTH, DISEASE AND AGEING