Matthias W. Hentze and Andreas E. Kulozik
Our research interest
Our team focuses on basic and translational aspects of RNA biology in common diseases such as the hemoglobin disorders, thrombosis, inflammation and childhood cancer. Specific areas of interest include the mechanism of nonsense-mediated decay (NMD), one of the cell’s key mRNA quality control pathways to limit the synthesis of faulty proteins, as well as the regulation of mRNA 3’ end processing and its response to stress.
We are also using transcriptomic and proteomic approaches to investigate the role of RNA-binding proteins (RBP) in cancer and their responses to pharmacological intervention.
Background
Initially, our group’s interest in RNA biology arose from detailed clinical analyses of two common hematological disorders, ß-thalassemia and thrombophilia, respectively. Interestingly, it is now becoming apparent that the principles that have been uncovered by the analysis of these two model conditions are applicable more generally.
Furthermore, the results of these projects have illustrated that the detailed analysis of unexplained medical phenomena can result in the identification and characterization of previously unrecognized basic biological mechanisms with broad implications.
With a continued focus on the “disease mechanisms aspect” of our work, future work will build on the maturity that this work has reached towards more translational aspects.
Goals
Our projects aim for deeper mechanistic understanding of RNA quality control by NMD and of regulated 3’ processing. Building on this, we aim to translate the mechanistic knowledge into an understanding of medically relevant pathways that lead to common human pathology. We also employ the recently developed RNA interactome capture technology (Castello et al., Cell, 2012) to study the role of RNA-binding proteins (RBP) in cancer and their responses to pharmacological intervention. These projects aim to uncover the role of RBPs in malignant disorders.
We wish to identify steps in the molecular pathogenesis of pediatric disorders that allow us to develop strategies for therapeutic intervention.
Selected publications
Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma.
Zhou Y, Ray PS, Zhu J, Stein F, Rettel M, Sekaran T, Sahadevan S, Perez-Perri JI, Roth EK, Myklebost O, Meza-Zepeda LA, von Deimling A, Fu C, Brosig AN, Boye K, Nathrath M, Blattmann C, Lehner B, Hentze MW, Kulozik AE.
Nat Commun. 2024 Apr 1;15(1):2810. doi: 10.1038/s41467-024-47031-y.PMID: 38561347
Blasticidin S inhibits mammalian translation and enhances production of protein encoded by nonsense mRNA.
Powers KT, Stevenson-Jones F, Yadav SKN, Amthor B, Bufton JC, Borucu U, Shen D, Becker JP, Lavysh D, Hentze MW, Kulozik AE, Neu-Yilik G, Schaffitzel C.
Nucleic Acids Res. 2021 Jul 21;49(13):7665-7679. doi: 10.1093/nar/gkab532. PMID: 34157102
NMD inhibition by 5-azacytidine augments presentation of immunogenic frameshift-derived neoepitopes.
Becker JP, Helm D, Rettel M, Stein F, Hernandez-Sanchez A, Urban K, Gebert J, Kloor M, Neu-Yilik G, von Knebel Doeberitz M, Hentze MW, Kulozik AE.
iScience. 2021 Apr 1;24(4):102389. doi: 10.1016/j.isci.2021.102389. eCollection 2021 Apr 23. PMID: 33981976
Pharmacological inhibition of nonsense-mediated RNA decay augments HLA class I-mediated presentation of neoepitopes in MSI CRC
Jonas P. Becker, Dominic Helm, Mandy Rettel, Frank Stein, Alejandro Hernandez-Sanchez, Katharina Urban, Johannes Gebert, Matthias Kloor, Gabriele Neu-Yilik, Magnus von Knebel Doeberitz, Matthias W. Hentze, Andreas E. Kulozik
bioRxiv:2020 Oct 13 doi: https://doi.org/10.1101/2020.10.13.319970
Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib.
Heidler CL, Roth EK, Thiemann M, Blattmann C, Perez RL, Huber PE, Kovac M, Amthor B, Neu-Yilik G, Kulozik AE.
Int J Cancer. 2020 Aug 15;147(4):1059-1070. doi: 10.1002/ijc.32814. Epub 2019 Dec 19. PMID: 31782150
(Phospho)proteomic Profiling of Microsatellite Unstable CRC Cells Reveals Alterations in Nuclear Signaling and Cholesterol Metabolism Caused by Frameshift Mutation of NMD Regulator UPF3A.
Michalak M, Katzenmaier EM, Roeckel N, Woerner SM, Fuchs V, Warnken U, Yuan YP, Bork P, Neu-Yilik G, Kulozik A, von Knebel Doeberitz M, Kloor M, Kopitz J, Gebert
J. Int J Mol Sci. 2020 Jul 23;21(15):5234. doi: 10.3390/ijms21155234. PMID: 32718059
UPF1-Mediated RNA Decay-Danse Macabre in a Cloud.
Lavysh D, Neu-Yilik G.
Biomolecules. 2020 Jul 4;10(7):999. doi: 10.3390/biom10070999. PMID: 32635561
Plasticity of nuclear and cytoplasmic stress responses of RNA-binding proteins
Michael Backlund, Frank Stein, Mandy Rettel, Thomas Schwarzl, Joel I Perez-Perri, Annika Brosig, Yang Zhou, Gabriele Neu-Yilik, Matthias W Hentze, Andreas E Kulozik
Nucleic Acids Research, 20 April 2020, gkaa256, https://doi.org/10.1093/nar/gkaa256
2,6-Diaminopurine as a highly potent corrector of UGA nonsense mutations.
Trzaska C, Amand S, Bailly C, Leroy C, Marchand V, Duvernois-Berthet E, Saliou JM, Benhabiles H, Werkmeister E, Chassat T, Guilbert R, Hannebique D, Mouray A, Copin MC, Moreau PA, Adriaenssens E, Kulozik A, Westhof E, Tulasne D, Motorin Y, Rebuffat S, Lejeune F.
Nat Commun. 2020 Mar 20;11(1):1509. doi: 10.1038/s41467-020-15140-z. PMID: 32198346
Discovery of RNA-binding proteins and characterization of their dynamic responses by enhanced RNA interactome capture.
Perez-Perri JI, Rogell B, Schwarzl T, Stein F, Zhou Y, Rettel M, Brosig A, Hentze MW.
Nat Commun. 2018 Oct 23;9(1):4408. doi: 10.1038/s41467-018-06557-8. PMID:30352994
Dual function of UPF3B in early and late translation termination
Gabriele Neu-Yilik, Etienne Raimondeau, Boris Eliseev, Lahari Yeramala, Beate Amthor, Aurélien Deniaud, Karine Huard, Kathrin Kerschgens, Matthias W. Hentze, Christiane Schaffitzel, Andreas E. Kulozik
EMBO J. 2017 Oct 16;36(20):2968-2986. doi: 10.15252/embj.201797079. Epub 2017 Sep 12. PMID:28899899
NOTCH1 mutation, TP53 alteration and myeloid antigen expression predict outcome heterogeneity in children with first relapse of T-cell acute lymphoblastic leukemia.
Hof J, Kox C, Groeneveld-Krentz S, Bandapalli OR, Karawajew L, Schedel K, Kunz JB, Eckert C, Ludwig WD, Ratei R, Rhein P, Henze G, Muckenthaler MU, Kulozik AE, von Stackelberg A, Kirschner-Schwabe R.
Haematologica. 2017 Jul;102(7):e249-e252. doi: 10.3324/haematol.2016.157792. Epub 2017 Mar 30. PMID: 28360149
Insights into the design and interpretation of iCLIP experiments.
Haberman N, Huppertz I, Attig J, König J, Wang Z, Hauer C, Hentze MW, Kulozik AE, Le Hir H, Curk T, Sibley CR, Zarnack K, Ule J.
Genome Biol. 2017 Jan 16;18(1):7. doi: 10.1186/s13059-016-1130-x. PMID: 28093074
Exon Junction Complexes Show a Distributional Bias toward Alternatively Spliced mRNAs and against mRNAs Coding for Ribosomal Proteins.
Hauer C, Sieber J, Schwarzl T, Hollerer I, Curk T, Alleaume AM, Hentze MW, Kulozik AE.
Cell Rep. 2016 Aug 9;16(6):1588-603. doi: 10.1016/j.celrep.2016.06.096. Epub 2016 Jul 28.
PMID: 27475226
The differential expression of alternatively polyadenylated transcripts is a common stress-induced response mechanism that modulates mammalian mRNA expression in a quantitative and qualitative fashion.
Hollerer I, Curk T, Haase B, Benes V, Hauer C, Neu-Yilik G, Bhuvanagiri M, Hentze MW, Kulozik AE.
RNA. 2016 Jul 12. [Epub ahead of print]
PMID: 27407180
Proteomic analysis reveals branch-specific regulation of the unfolded protein response by nonsense-mediated mRNA decay
Sieber, J., Hauer, C., Bhuvanagiri, M., Leicht, S., Krijgsveld, J., Neu-Yilik, G., Hentze, M.W., Kulozik, A.E.
Molecular & Cellular Proteomics 2016 Feb 20 pii: mcp.M115.054056.
Improved binding site assignment by high-resolution mapping of RNA-protein interactions using iCLIP.
Hauer C, Curk T, Anders S, Schwarzl T, Alleaume AM, Sieber J, Hollerer I, Bhuvanagiri M, Huber W, Hentze MW, Kulozik AE.
Nat Commun. 2015 Aug 11;6:7921. doi: 10.1038/ncomms8921. PMID: 26260686
A network of SMG-8, SMG-9 and SMG-1 C-terminal insertion domain regulates UPF1 substrate recruitment and phosphorylation.
Deniaud A, Karuppasamy M, Bock T, Masiulis S, Huard K, Garzoni F, Kerschgens K, Hentze MW, Kulozik AE, Beck M, Neu-Yilik G, Schaffitzel C.
Nucleic Acids Res. 2015 Jun 30. pii: gkv668.
The best of 25 years: mRNA 3’end processing.
Hollerer I, Kulozik AE.
RNA. 2015 Apr;21(4):640-1. doi: 10.1261/rna.050062.115
5-azacytidine inhibits nonsense-mediated decay in a MYC-dependent fashion.
Bhuvanagiri M, Lewis J, Putzker K, Becker JP, Leicht S, Krijgsveld J, Batra R, Turnwald B, Jovanovic B, Hauer C, Sieber J, Hentze MW, Kulozik AE.
EMBO Mol Med. 2014 Oct 15. pii: e201404461. doi: 10.15252/emmm.201404461.
mRNA 3’end processing: A tale of the tail reaches the clinic
Ina Hollerer, Kerstin Grund, Matthias W. Hentze, Andreas E. Kulozik
EMBO Mol Med. 2014 Jan 1;6(1):16-26. doi: 10.1002/emmm.201303300.
Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond.
Danckwardt S, Hentze MW, Kulozik AE.
J Mol Med (Berl). 2013 Aug 17.
Two mammalian MAGOH genes contribute to exon junction complex composition and nonsense-mediated decay.
Singh KK, Wachsmuth L, Kulozik AE, Gehring NH._
RNA Biol. 2013 Aug 1;10(8):1291-1298. Epub 2013 Jul 23_
Notch1 activation clinically antagonizes the unfavorable effect of pten inactivation in bfm-treated children with precursor t-cell acute lymphoblastic leukemia.
Bandapalli OR, Zimmermann M, Kox C, Stanulla M, Schrappe M, Ludwig WD, Koehler R, Muckenthaler MU, Kulozik AE
Haematologica 2013 Jun;98:928-936
Krebs, Blutgerinnung und Stress –eine ungewöhnliche Ménage-à-trois
Matthias W. Hentze und Andreas E. Kulozik
Spektrum der Wissenschaft, Juli 2012
Stay tuned: miRNA expression and nonsense-mediated decay in brain development.
Kulozik AE.
Mol Cell. 2011 May 20;42(4):407-8
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Mechanism of escape from nonsense-mediated mRNA decay of human {beta}-globin transcripts with nonsense mutations in the first exon.
Neu-Yilik G, Amthor B, Gehring NH, Bahri S, Paidassi H, Hentze MW, Kulozik AE.
RNA. 2011 May;17(5):843-54. Epub 2011 Mar 9
p38 MAPK controls prothrombin expression by regulated RNA 3′ end processing.
Danckwardt S, Gantzert AS, Macher-Goeppinger S, Probst HC, Gentzel M, Wilm M, Gröne HJ, Schirmacher P, Hentze MW, Kulozik AE.
Mol Cell. 2011 Feb 4;41(3):298-310
ALL can be separated from NOTCH pathway activation by FBXW7 loss of function.
Kox, C, M. Zimmermann, M. Stanulla, M. S. Leible, M. Schrappe, W.-D. Ludwig, M. Muckenthaler, A.E. Kulozik.
Leukemia. 2010 Dec;24(12):2005-13. Epub 2010 Oct 14
Taking childhood leukemia personally.
Kulozik AE.
Blood. 2010 Dec 2;116(23):4737-8
NMD: RNA biology meets human genetic medicine.
Bhuvanagiri, M, A. M. Schlitter, M. W. Hentze, A. E. Kulozik.Biochemical Journal (2010) Aug 27;430(3):365-77
Disassembly of exon junction complexes by PYM.
Gehring N.H., S. Lamprinaki, A.E. Kulozik, M.W. Hentze.
Cell. 2009 May 1;137(3):536-48
The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay
Gehring NH, Lamprinaki S, Hentze MW, Kulozik AE.PLoS Biol. 2009 May 26;7(5):e1000120. Epub 2009 May 26
Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways.
Ivanov P., N. Gehring, J. Kunz, M.W. Hentze, A.E. Kulozik.
EMBO J. 2008 Mar 5;27(5):736-47. Epub 2008 Feb 7.
3′ end mRNA processing: Molecular mechanisms and implications for health and disease.
Danckwardt, S., M.W. Hentze, A.E. Kulozik.
EMBO J. 2008 Feb 6;27(3):482-98.
Splicing factors stimulate polyadenylation via USEs at non-canonical 3’ end formation signals.
Danckwardt, S., I. Kaufmann, M. Gentzel, K. Förstner, A.S. Gantzert, N.H. Gehring, G. Neu-Yilik, P. Bork, W. Keller, M. Wilm, M.W. Hentze, A.E. Kulozik.EMBO J. 2007 Jun 6;26(11):2658-69. Epub 2007 Apr 26.
